Microbiology Devices; Reclassification of Antigen, Antibody, and Nucleic Acid-Based Hepatitis B Virus Assay Devices

SUPPLEMENTARY INFORMATION:

I. Background—Regulatory Authorities

The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended, establishes a comprehensive system for the regulation of medical devices intended for human use. Section 513 of the FD&C Act (21 U.S.C. 360c) established three categories (classes) of devices, reflecting the regulatory controls needed to provide reasonable assurance of their safety and effectiveness. The three categories of devices are class I (general controls), class II (general controls and special controls), and class III (general controls and premarket approval).

Section 513(a)(1) of the FD&C Act defines the three classes of devices. Class I devices are those devices for which the general controls of the FD&C Act (controls authorized by or under sections 501, 502, 510, 516, 518, 519, or 520 (21 U.S.C. 351, 352, 360, 360f, 360h, 360i, or 360j) or any combination of such sections) are sufficient to provide reasonable assurance of safety and effectiveness; or those devices for which insufficient information exists to determine that general controls are sufficient to provide reasonable assurance of safety and effectiveness or to establish special controls to provide such assurance, but because the devices are not purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health, and do not present a potential unreasonable risk of illness or injury, are to be regulated by general controls (section 513(a)(1)(A) of the FD&C Act). Class II devices are those devices for which general controls by themselves are insufficient to provide reasonable assurance of safety and effectiveness, and for which there is sufficient information to establish special controls to provide such assurance, including the issue of performance standards, postmarket surveillance, patient registries, development and dissemination of guidelines, recommendations, and other appropriate actions the Agency deems necessary to provide such assurance (section 513(a)(1)(B) of the FD&C Act). Class III devices are those devices for which insufficient information exists to determine that general controls and special controls would provide a reasonable assurance of safety and effectiveness, and are purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health, or present a potential unreasonable risk of illness or injury (section 513(a)(1)(C) of the FD&C Act).

Devices that were not in commercial distribution before May 28, 1976 (generally referred to as “postamendments devices”) are automatically classified by section 513(f)(1) of the FD&C Act into class III without any FDA rulemaking process. Those devices remain in class III and require premarket approval, unless, and until: (1) FDA reclassifies the device into class I or II, or (2) FDA issues an order finding the device to be substantially equivalent, in accordance with section 513(i) of the FD&C Act, to a predicate device that does not require premarket approval. The Agency determines whether new devices are substantially equivalent to predicate devices by means of the premarket notification procedures in section 510(k) of the FD&C Act and part 807, subpart E (21 CFR part 807, subpart E) of FDA's regulations.

A postamendments device that has been initially classified in class III under section 513(f)(1) of the FD&C Act may be reclassified into class I or class II under section 513(f)(3) of the FD&C Act. Section 513(f)(3) of the FD&C Act provides that FDA, acting by administrative order, can reclassify the device into class I or class II on its own initiative, or in response to a petition from the manufacturer or importer of the device. To change the classification of the device, the proposed new class must have sufficient regulatory controls to provide reasonable assurance of the safety and effectiveness of the device for its intended use.

FDA relies upon “valid scientific evidence”, as defined in section 513(a)(3) of the FD&C Act and 21 CFR 860.7(c)(2), in the classification process to determine the level of regulation for devices. To be considered in the reclassification process, the “valid scientific evidence” upon which the Agency relies must be publicly available (see section 520(c) of the FD&C Act). Publicly available information excludes trade secret and/or confidential commercial information, e.g., the contents of a pending premarket approval application (PMA) (see section 520(c) of the FD&C Act).

In accordance with section 513(f)(3) of the FD&C Act, FDA is issuing this proposed order to reclassify qualitative HBV antigen assays intended for qualitative detection of HBV antigens as an aid in the diagnosis of acute or chronic HBV infection in specific populations, HBV antibody assays (including qualitative and quantitative anti-HBs) intended for use in the detection of antibodies to HBV, and quantitative HBV nucleic acid-based assays intended for use in the detection of HBV nucleic acid in specimens from individuals with antibody evidence of HBV infection, all of which are postamendments class III devices, into class II (general controls and special controls) subject to premarket notification, under three new device classification regulations with the names “Qualitative Hepatitis B Virus Antigen Assays,” “Hepatitis B Virus Antibody Assays,” and “Hepatitis B Virus Nucleic Acid-Based Assays.” FDA believes the standard in section 513(a)(1)(B) of the FD&C Act is met as there is sufficient information to establish special controls, which, in addition to general controls, will provide reasonable assurance of the safety and effectiveness of these devices.

Section 510(m) of the FD&C Act provides that FDA may exempt a class II device from the premarket notification requirements under section 510(k) of the FD&C Act, if FDA determines that premarket notification is not necessary to provide reasonable assurance of the safety and effectiveness of the device. FDA has determined that premarket notification is necessary to provide a reasonable assurance of the safety and effectiveness of HBV antigen assays, HBV antibody assays, and HBV nucleic acid-based assays for their intended uses, therefore, the Agency does not intend to exempt these proposed class II devices from the requirement for premarket notification (510(k)) submission as provided under section 510(m) of the FD&C Act. If this proposed order is finalized, persons who intend to market this type of device must submit to FDA a premarket notification under section 510(k) of the FD&C Act prior to marketing the device.

II. Regulatory History of the Devices

Under section 513(f)(1) of the FD&C Act, qualitative HBV antigen assays, HBV antibody assays (including qualitative and quantitative anti-HBs), and quantitative HBV nucleic acid-based assays are automatically classified into class III because they were not introduced or delivered for introduction into interstate commerce for commercial distribution before May 28, 1976, and have not been found substantially equivalent to a device placed in commercial distribution after May 28, 1976, which was subsequently classified or reclassified into class II or class I. Therefore, they are subject to PMA requirements under section 515 of the FD&C Act (21 U.S.C. 360e). Qualitative HBV antigen assays and HBV antibody assays (including qualitative and quantitative anti-HBs) are prescription devices and assigned product code LOM. Quantitative HBV nucleic acid-based assays are prescription devices and assigned product code MKT.

A. Qualitative HBV Antigen Assays

The first proposed device reclassification action applies to qualitative HBV antigen assay devices that are prescription in vitro diagnostic devices intended for qualitative detection of HBV antigens as an aid in the diagnosis of acute or chronic HBV infection in specific populations. On February 8, 2001, FDA approved its first HBV antigen assay (DiaSorin's ETI-EBK PLUS) for use in the qualitative detection of hepatitis Be antigen (HBeAg) in human serum or plasma (ethylenediaminetetraacetic acid (EDTA), citrate, or heparin) as indicative of a laboratory diagnosis of HBV infection through its PMA process under section 515 of the FD&C Act. On June 1, 2001, FDA approved its first HBV surface antigen (HBsAg) assay (Roche Elecsys HBsAg Immunoassay, Elecsys HBsAg Confirmatory, and Precicontrol HBsAg) for the qualitative detection of HBsAg in human serum or plasma (heparin, EDTA, sodium citrate) in adult pregnant and non-pregnant individuals. In a May 22, 2002, Federal Register notice (67 FR 36009), FDA announced the approval order and the availability of the Summary of Safety and Effectiveness Data (SSED) for these devices. Since the first approval order for an HBV antigen assay issued on February 8, 2001, FDA has approved 16 additional original PMAs for qualitative HBV antigen assays that are prescription devices intended for the detection of HBV antigens. These assays are intended as an aid in the diagnosis of acute or chronic HBV infection in conjunction with clinical findings and other diagnostic procedures ( e.g., HBV serology and antigen testing, liver function, etc.). These assays are not intended for use in screening of blood, plasma, cells, or tissue donors.

A review of the medical device reporting (MDR) databases indicates that there were 625 reported events for qualitative HBV antigen assays as of June 2024. Of these reported events, a significant majority of these were determined to be of no known impact or consequence to the patient. Events reported included false reactive results, false non-reactive results, incorrect or inadequate assay results, incorrect/inadequate/imprecise readings, improper or incorrect procedure or method, device operates differently than expected, and adverse event without identified device or use problems. Where incorrect results were obtained, it was not clear what the correct result should have been. As of June 2024, there have been no class III recalls, six class II recalls, and no class I recalls involving qualitative HBV antigen assays. The class II recalls occurred since 2006 due to defective caps, device design, no marketing application, signal for reactive results, and biased results for biotin concentrations that were lower than indicated. No patient harm was identified. These facts, coupled with the low number of reported events that caused patient harm, indicate a good safety record for this device class. These recall events reflect the risks to health identified in section V below, and FDA believes the special controls proposed herein, in addition to general controls, can effectively mitigate the risks identified in these recalls.

B. HBV Antibody Assays (Including Qualitative and Quantitative Anti-HBs)

The second type of devices this proposed reclassification order applies to are qualitative HBV antibody assays and quantitative anti-HBs assays that are prescription in vitro diagnostic devices intended for use in the detection of antibodies to HBV. These devices are intended to aid in the diagnosis of HBV infection in persons with signs and symptoms of hepatitis and in persons at risk for HBV infection. On September 29, 2000, FDA approved its first qualitative HBV antibody assay (Ortho-Clinical Diagnostics, Inc.'s Vitros Immunodiagnostic Products: Anti-HBS Reagent Pack/Anti-HBS Calibrators) for the qualitative in vitro determination of total antibody to hepatitis B surface antigen (anti-HBs) in human serum as an aid in determining susceptibility to HBV infection for individuals prior to or following HBV vaccination, or where vaccination status is unknown, and for use with other HBV serological markers for the laboratory diagnosis of HBV disease associated with HBV infection, through its PMA process under section 515 of the FD&C Act. In a March 12, 2001, Federal Register notice (66 FR 14390), FDA announced the approval order and the availability of the SSED for this device. On July 22, 2002, FDA approved its first quantitative Anti-HBs (Siemens Healthcare Diagnostics Products Ltd.'s Immulite 2000 XPI Anti-HBs) for the quantitative measurement of total antibodies to the hepatitis B surface antigen (anti-HBs) in human serum and plasma (heparinized or EDTA) as an aid in the determination of susceptibility to HBV infection for individuals prior to or following HBV vaccination, or where vaccination status is unknown, or for use with other HBV serological markers for the laboratory diagnosis of HBV disease associated with HBV infection, through its PMA process under section 515 of the FD&C Act.

Since the first approval order of a qualitative HBV antibody assay on September 29, 2000, FDA has approved 31 additional original PMAs for qualitative HBV antibody assays for the detection of antibodies to HBV. FDA has also approved six assays for quantitative anti-HBs detection. Qualitative HBV antibody assays and quantitative anti-HBs assays are intended to aid in the diagnosis of HBV infection in persons with signs and symptoms of hepatitis and in persons at risk for HBV infection in conjunction with clinical findings and other diagnostic procedures ( e.g., HBV serology and antigen testing, liver function, etc.). These assays are not intended for use in screening of blood, plasma, cells, or tissue donors.

A review of the MDR databases indicates that there were 1,107 reported events for HBV antibody assays between years 2001 and June 2024. Of these reported events, a significant majority of these were of no known impact to the patient, and only four resulted in impact to patients such as misdiagnosis or viral infection. Events reported included adverse events without identified device or use problem, disconnection/low assay results, false non-reactive results, false reactive results, false high assay results (for example, the first assay result had a low signal to cutoff (s/co) value and repeat testing produced a higher s/co value), incorrect assay results, inadequate assay results, and low assay results (for example, the first assay result was in the equivocal zone, repeat testing produced a non-reactive result, and testing with an alternate device produced a reactive result). In numerous cases, it was not possible to determine what the correct result should have been (further testing was not performed, insufficient sample volume, different assays were used). As of June 2024, FDA is aware of 4 class III recalls, 12 class II recalls, and no class I recalls for these devices. The class II recalls occurred in 2007, 2008, 2009, 2011, 2012, 2013, 2014, 2018, and 2019, and were related to issues such as false reactive results, false high assay results, defective caps, and errors in labeling, packaging, or software. No patient harm has been identified. These facts, coupled with the low number of reported events that impacted the patient, indicate a good safety record for this device class. These recall events reflect the risks to health identified in section V below, and FDA believes the special controls proposed herein, in addition to general controls, can effectively mitigate the risks identified in these recalls.

C. Quantitative HBV Nucleic Acid-Based Assays

Finally, the third type of device this proposed reclassification order applies to are quantitative HBV nucleic acid-based assay devices for use as a prescription in vitro diagnostic device intended for use in the detection of HBV nucleic acid in specimens from individuals with antibody evidence of HBV infection. On September 4, 2008, FDA approved its first quantitative HBV nucleic assay (Roche Molecular Systems, Inc.'s COBAS TaqMan HBV Test For Use With The High Pure System), an in vitro nucleic acid amplification assay for the quantitation of HBV deoxyribonucleic acid (DNA) in human serum or plasma (EDTA) intended for use as an aid in the management of patients with chronic HBV infection undergoing antiviral therapy, through its PMA process under section 515 of the FD&C Act.

Since the first approval order, FDA has approved four additional original PMAs for quantitative HBV nucleic acid-based assays for the quantitative detection of HBV DNA. The detection of HBV DNA is used for management of patients undergoing antiviral therapy for assessing response to treatment and not as a diagnostic for HBV infection.

The following section provides examples of the different technologies used. The different technologies begin with specimen lysis and HBV DNA through hybridization with magnetic particles. The differences in the technologies occur with the method of amplification:

• In one technology, the target HBV DNA sequence is amplified. The presence of HBV amplification products is detected by measuring the fluorescence of the HBV probe that binds to the target. Similarly, the presence of the internal control amplification product is detected. In the absence of HBV or internal control target sequences, probe fluorescence is quenched. In the presence of HBV or internal control target, the HBV or internal control probes bind to their target.
• In another technology, target amplification occurs via transcription-based nucleic acid amplification by fluorescent labeled probes (torches). More torches hybridize when more amplicon is present creating a higher fluorescent signal. The time taken for the fluorescent signal to reach a threshold proportional to the starting HBV DNA concentration is measured in relation to internal controls.

A review of the MDR databases indicates that as of June 2024 there were 13 reported events for nucleic acid-based HBV DNA assays since the first reported event in 2009. MDRs were for the following reasons: (1) incorrect, inadequate, or imprecise result or readings; (2) high readings; and (3) non-reproducible results. Of these, two had no known impact or consequence to the patient and two occurred when the patient had no signs, symptoms, or conditions. As of June 2024, FDA is aware of one class III recall, five class II recalls, and no class I recalls for these devices. The class II recalls occurred between 2005 and 2022 and were related to issues such as misquantitation of high results for negative samples (carryover from a high positive sample tested adjacent to a negative sample may produce an incorrect positive result), liquid level detection of reagent cassette, under filled and over filled enzyme reagent vials in assay kits, software, and low level of recombinant HBV DNA found in one lot of reagent. These facts, coupled with the low number of reported events that impacted the patient, indicate a good safety record for this device class. These recall events reflect the risks to health identified in section V below, and FDA believes the special controls proposed herein, in addition to general controls, can effectively mitigate the risks identified in these recalls.

III. Device Description

The HBV assays that are the subject of this proposed order are postamendments prescription in vitro diagnostic devices classified into class III under section 513(f)(1) of the FD&C Act.

A. Qualitative HBV Antigen Assays

A qualitative HBV antigen assay is a prescription in vitro diagnostic device intended for use in the qualitative detection of HBV antigens and for use as an aid in the diagnosis of HBV infection in specific populations. HBV antigen assays aid in the diagnosis of acute or chronic HBV infection. HBV antigen assays typically detect the presence of Hepatitis B surface antigen (HBsAg) or Hepatitis B e antigen (HBeAg). HBV antigens (HBsAg and HBeAg), when present in samples, bind to anti-HBs or anti-HBe antibodies to form a complex that is bound to a solid phase ( e.g., microparticles, microtiter plate or other technology). Detection of the complexes can be performed using different methods which measure the presence/absence of anti-HBs or anti-HBe antibodies in the sample.

Diagnosis of HBV infection should not be established based on a single assay result but should be determined in conjunction with clinical findings and other diagnostic procedures ( e.g., HBV serology and antigen testing, liver function, etc.). These assays are not intended for use in screening of blood, plasma, cells, or tissue donors.

B. HBV Antibody Assays (Including Qualitative and Quantitative Anti-HBs)

A qualitative HBV antibody assay is a prescription in vitro diagnostic device intended for use in the qualitative detection of antibodies to HBV and for use as an aid in the diagnosis of HBV infection in specific populations. HBV antibody assays aid in the diagnosis of HBV infection in persons with signs and symptoms of hepatitis and in persons at risk for HBV infection. Antibody assays typically detect the presence of antibodies to HBsAg (anti-HBs), Hepatitis B core antigen (anti-HBc), or HBeAg (anti-HBe). Diagnosis of HBV infection should not be established based on a single assay result, but should be determined in conjunction with clinical findings and other diagnostic procedures ( e.g., HBV serology and antigen testing, liver function, etc.). These assays are not intended for use in screening of blood, plasma, cells, or tissue donors.

A quantitative assay that detects anti-HBs (antibodies to HBV surface antigen (HBsAg)) is a prescription in vitro diagnostic device that is intended for quantitative use to aid in the diagnosis of HBV infection in persons with signs and symptoms of hepatitis and in persons at risk for HBV infection. Detection of anti-HBs indicates a present or past infection with HBV and can be used in conjunction with clinical findings such as other HBV serological markers (detection of other HBV antigens and antibodies to HBV) for diagnosis of HBV infection. Anti-HBs assay results may be used as an aid in the determination of susceptibility to HBV infection in individuals prior to vaccination or when vaccination status is unknown.

In some device designs, HBV antibodies, when present in the sample, bind to HBV antigens to form a complex that is bound to a solid phase ( e.g., microparticles, microtiter plate, or other technology). Detection of complexes can be performed using different methods that measure the presence/absence of HBV antibodies in the sample.

C. Quantitative HBV Nucleic Acid-Based Assays

A quantitative HBV nucleic acid-based assay is a prescription in vitro diagnostic device intended for 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 for management of patients undergoing antiviral therapy for assessing response to treatment and NOT as a diagnostic for HBV infection.

FDA is proposing to reclassify qualitative HBV antigen, HBV antibody assays (including qualitative and quantitative anti-HBs), and quantitative HBV nucleic acid-based assays from class III (general controls and premarket approval) to class II (general controls and special controls) and to establish new names for the device types that will be within the classification regulations. FDA proposes to revise 21 CFR part 866 to create three new device classification regulations with the names “Qualitative Hepatitis B Virus Antigen Assays,” “Hepatitis B Virus Antibody Assays,” and “Hepatitis B Virus Nucleic Acid-Based Assays.” FDA believes that these names and proposed identification language most accurately describe these devices.

• A Qualitative Hepatitis B Virus (HBV) Antigen Assay is tentatively 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.
• A Hepatitis B Virus (HBV) Antibody Assay is tentatively identified as an in vitro diagnostic device intended for prescription use in the detection of antibodies to HBV in human serum and plasma, or other matrices, and or as an aid in the diagnosis of HBV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis B infection. In addition, anti-HBc IgM (IgM antibodies to core antigen) assay is 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.
• A Hepatitis B Virus (HBV) Nucleic Acid-Based Assay is tentatively 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.

Based upon our review experience and consistent with the FD&C Act and FDA's regulations in 21 CFR 860.134, FDA believes that these devices should be reclassified from class III into class II with special controls because there is sufficient information to establish special controls that, along with general controls, can provide reasonable assurance of the devices' safety and effectiveness.

IV. Proposed Reclassification and Summary of Reasons for Reclassification

FDA is proposing to reclassify the HBV assays that are the subject of this proposed order. On September 7, 2023, the Microbiology Devices Panel (Panel) of the Medical Devices Advisory Committee convened to discuss and make recommendations regarding the reclassification of HBV assays from class III (general controls and premarket approval) to class II (general controls and special controls) ( https://www.fda.gov/media/173609/download ). Panel members unanimously agreed that special controls, in addition to general controls, are necessary and sufficient to mitigate the risks to health of patients presented by these devices and to provide reasonable assurance of the safety and effectiveness of these devices (Refs. 1 and 2). The Panel agreed with FDA-identified risks and identified additional risk(s) and benefit(s) to include in the overall risk assessment. The Panel also discussed potential mitigation measure(s)/control(s) FDA should consider for each of the identified risks and recommended that, as part of any reclassification, the expected performance for these devices should remain the same. Notably, the performance of approved HBV antigen assays has generally been at least 97 percent sensitivity and 99 percent specificity. For approved anti-HBs, anti-Hbe, and anti-HBc total assays the sensitivity has generally been at least 95 percent, for approved anti-HBc IgM assays the sensitivity has been at least 86 percent, and for all HBV approved antibody assays the specificity has generally been above 97 percent.

FDA believes that at this time, sufficient data and information exist such that the risks identified in section V below can be mitigated by establishing special controls, and that these special controls, together with general controls, are necessary to provide a reasonable assurance of the safety and effectiveness of these HBV assays and therefore proposes these devices to be reclassified from class III (general controls and premarket approval) to class II (general controls and special controls). In accordance with section 513(f)(3) of the FD&C Act and 21 CFR part 860, subpart C, FDA is proposing to reclassify qualitative HBV antigen assays, HBV antibody assays (including qualitative and quantitative anti-HBs), and quantitative HBV nucleic acid-based assays from class III into class II, subject to premarket notification (510(k)) requirements. FDA believes that there is sufficient information available to FDA through FDA's accumulated experience with these devices from reviewing the PMAs for these HBV assays, and the Panel considerations and recommendations regarding the proposed special controls that FDA believes would effectively mitigate the risks to health identified in section V. Absent the special controls identified in this proposed order, general controls applicable to the devices are insufficient to provide reasonable assurance of the safety and effectiveness of the devices. FDA expects that the reclassification of these devices would enable more manufacturers to develop these assays such that patients would benefit from increased access to safe and effective tests.

FDA is proposing to create three separate classification regulations for HBV assays that will be reclassified from class III to class II. HBV assays are prescription in vitro diagnostic devices, and under this proposed order, if finalized, these devices will be identified as prescription in vitro diagnostic devices. As such, the devices must satisfy prescription labeling requirements for in vitro diagnostic products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)). In this proposed order, if finalized, FDA has identified the special controls under section 513(a)(1)(B) of the FD&C Act that, together with general controls, will provide a reasonable assurance of the safety and effectiveness of these assays.

FDA is also proposing to create a new product code for HBV antibody assays (including qualitative and quantitative anti-HBs) that will be assigned upon any finalization of this proposed order. Qualitative HBV antigen assays will continue to be assigned the product code LOM upon any finalization of this proposed order.

Section 510(m) of the FD&C Act provides that FDA may exempt a class II device from the premarket notification requirements under section 510(k) of the FD&C Act, if FDA determines that premarket notification is not necessary to provide reasonable assurance of the safety and effectiveness of the device. For these HBV assays, FDA has determined that premarket notification is necessary to provide a reasonable assurance of the safety and effectiveness of these devices. Therefore, the Agency does not intend to exempt these proposed class II devices from 510(k) requirements. If this proposed order is finalized, persons who intend to market a new HBV assay will no longer need to have a PMA for these devices but can instead submit to FDA a 510(k) and receive clearance prior to marketing the device. A 510(k) typically results in a shorter premarket review timeline compared to a PMA, which ultimately provides more timely access of these types of devices to patients.

V. Public Health Benefits and Risks to Health

FDA is providing a substantive summary of the valid scientific evidence concerning the public health benefits of the use of HBV assays (see also https://www.fda.gov/media/171770/download ), and the nature (and if known, the incidence) of the risks of the devices (see further discussion of the special controls being proposed to mitigate these risks in section VII of this proposed order).

HBV infection represents a significant global public health burden. According to the World Health Organization (WHO), in 2019 there were approximately 296 million people chronically infected people worldwide, with 1.5 million new HBV infections each year. It is estimated by the Centers for Disease Control and Prevention (CDC) that chronic HBV infection in the United States affects at least between 580,000 to 1.17 million people with HBV infection in the United States; two-thirds of whom may be unaware of their infection. HBV infection can be asymptomatic, and accordingly, many HBV-infected individuals are unaware of their HBV infection. Approximately 95 percent of adult patients with acute infection, defined as the first 6 months after infection, recover completely, and 5 percent of adults develop chronic HBV. Infants born to women who are HbsAg-positive are at high risk of HBV infection. In absence of treatment, infants infected with HBV have a 90 percent risk of progression to chronic HBV and up to 25 percent of infants who acquire chronic HBV infection will die prematurely from HBV-related hepatocellular carcinoma or cirrhosis. Patients who are tested and become aware that they are HBV infected may modify risk behaviors to prevent transmission to others and can be referred for treatment. Patients with chronic HBV infection have a risk of developing liver damage, liver cancer, or liver failure. They can also spread their infection to others. HBV can be reactivated in patients receiving immunosuppressive therapies, resulting in serious risk of liver failure or liver-associated death (Ref. 3). HBV is a vaccine-preventable liver infection.

With the initiation of the WHO Viral Hepatitis Elimination Plan and the Department of Health and Human Services (HHS) Viral Hepatitis National Strategic Plan for the United States, it is important for individuals to know their HBV infected status, to link HBV infected individuals to care, and to eliminate virus transmission. Therefore, diagnosis of patients with HBV infection through devices such as HBV antibody and antigen assays is essential to ensure that patients are linked to the appropriate care. Current CDC HBV Screening and Testing Recommendations include testing of the following groups: all adults 18 and older at least once in their lifetime using a triple panel test, pregnant women during pregnancy, people who are at ongoing risk for exposure, and anyone who requests HBV testing.

FDA considered our accumulated experience with the regulation of these HBV assays, input from the Panel meeting, and postmarket information regarding these HBV assays, i.e., information from FDA's publicly available MDR, Manufacturer and User Facility Device Experience (MAUDE), and Medical Device Recall databases.

These HBV assays provide a benefit to the public health by informing individuals of their HBV infected status, linking HBV infected individuals to appropriate care, and aiding in eliminating virus transmission. Once an individual is tested and diagnosed as HBV infected, HBV nucleic acid testing is performed to inform treatment decisions. While HBV infection is treatable, it is not curable, which means that most people who start HBV antiviral treatment must continue it for life. The goal of current treatment is to suppress the virus and reduce the likelihood of long-term complications and transmission (Refs. 3 and 4). Thus, identifying individuals who are HBV infected, linking them to care, and managing their HBV infection to alleviate development of liver damage, liver cancer, liver failure, and potential HBV transmission would not only greatly impact public health but also go a long way towards helping the United States achieve HBV elimination.

Probable risks to health associated with the use of HBV assays include risks related to the risk of false results (false positives, false negatives, inaccurate low assay results, inaccurate high assay results, false reactive results, or false non-reactive results), failure to correctly interpret assay results, and failure to correctly operate the device. For HBV antigen and antibody assays, false positive results are generally referred to as false reactive results and false negative results are generally referred to as false non-reactive results. False results can lead to uninfected individuals receiving unnecessary further testing and treatment or infected individuals remaining undiagnosed and untreated. Undiagnosed and untreated individuals are likely to experience increases in morbidity and mortality and can spread the infection to others. FDA has identified the following additional specific risks to health associated with each of the HBV assays listed below.

A. Qualitative HBV Antigen Assays

Factors that may cause decreased assay sensitivity and/or an increased rate of false non-reactive results include, but are not limited to, the presence of interfering substances in the sample, acute infection at a stage that is too early for a device to detect the infection, and antigen concentrations that are too low to be detected by the device. Factors that may lead to false reactive results include device contamination from reactive samples, cross-reactivity with other antigens, or misinterpretation of invalid results as reactive.

• A false reactive assay result for HbeAg. Incorrectly interpreting the assay results as a reactive assay result or failing to correctly operate the assay causing a false reactive assay result may lead to continued treatment for hepatitis B with antiviral medication when it otherwise would not be indicated. Antiviral medication has risks including toxicity and more rarely allergic reactions. Over time, viral resistance in patients who are co-infected but undiagnosed with other viruses that are treated with the same antiviral medication, such as HIV, can lead to viral resistance.
• A false reactive assay result for HbsAg. Incorrectly interpreting the assay results as a reactive assay result or failing to correctly operate the assay causing a false reactive assay result may contribute to unnecessary additional testing, potentially delaying diagnosis of alternative causes of liver disease when present and may impact the psychological well-being of the patient. Factors that may increase the rate of false reactive assay reporting include cross-reactivity with antigens from other microorganisms or other disease conditions.
• A false non-reactive result for HbeAg. Incorrectly interpreting the assay results as a non-reactive assay result or failing to correctly operate the assay causing a false non-reactive assay result may lead to missing the opportunity for treatment of an HBV infected individual with antiviral medication or premature discontinuation of antiviral treatment when continuation of treatment is otherwise indicated should a clinician be falsely led to determine a patient has seroconverted HbeAg to anti-Hbe. Premature discontinuation of antiviral medication could result in adverse effects on patient health, such as cirrhosis, liver cancer, and liver damage, all of which are known to contribute to patient morbidity and mortality, or may contribute to public health risk by leading to virus transmission.
• A false non-reactive assay result for HbsAg. Incorrectly interpreting the assay results as a non-reactive assay result or failing to correctly operate the assay causing a false non-reactive assay result may delay or prevent a patient with HBV infection from being identified and linked to care. Missed identification of patients with chronic HBV infection could lead to adverse effects on patient health such as cirrhosis, liver cancer, and liver damage, all of which are known to contribute to patient morbidity and mortality. A false non-reactive HbsAg assay incorrectly interpreted as non-reactive also may contribute to public health risk by leading to virus transmission.

B. HBV Antibody Assays (Including Qualitative and Quantitative Anti-HBs)

Factors that may cause decreased assay sensitivity and/or an increased rate of false non-reactive results include, but are not limited to, the presence of interfering substances in the sample, acute infection at a stage that is too early for a device to detect the infection, and antibody concentrations that are too low to be detected by the device. They also can be caused by misinterpretation of invalid results as non-reactive. Factors that may lead to false reactive results include device contamination from reactive samples, cross-reactivity with other antibodies, or misinterpretation of invalid results as reactive.

• A false reactive assay result for anti-HBs and anti-HBc. Incorrectly interpreting the assay results as a reactive assay result or failing to correctly operate the assay causing a false reactive assay result may lead to improper patient management. A false reactive antibody assay result could result in the unnecessary continuation of antiviral treatment. Antiviral medication has risks including toxicity and more rarely allergic reactions. Over time, viral resistance in patients who are co-infected but undiagnosed with other viruses that are treated with the same antiviral medication, such as HIV, can lead to viral resistance. Consequently, repeatedly false reactive results have the potential to lead to inappropriate patient management decisions.
• A false reactive assay result for anti-HBs. Incorrectly interpreting the assay results as a reactive assay result or failing to correctly operate the assay causing a false reactive assay result when the device is used as an aid in the determination of susceptibility to HBV infection in individuals prior to or following HBV vaccination or where vaccination status is unknown may cause a patient to be considered previously exposed and therefore immune to HBV or that the patient was successfully vaccinated. A false reactive result may cause the patient to not receive a vaccine, vaccine booster, hyperimmune globulin, and would be at higher risk of infection if exposed to HBV.
• A false reactive assay result for anti-Hbe. Incorrectly interpreting the assay results as a reactive assay result, or failing to correctly operate the assay causing a false reactive assay result may lead to missing the opportunity for treatment of HBV infection with antiviral medications in a subset of individuals for whom treatment would otherwise be indicated, or premature discontinuation of antiviral treatment when continuation of treatment is otherwise indicated should a clinician be falsely led to determine a patient has seroconverted HbeAg to anti-Hbe. Premature discontinuation of antiviral medication could result in adverse effects on patient health such as cirrhosis, liver cancer, and liver damage, all of which are known to contribute to patient morbidity and mortality, or may contribute to public health risk by leading to inadvertent transmission of virus by an infected individual.
• A false non-reactive assay result for anti-HBc. When the device is used as an aid in the diagnosis of HBV infection in patients with symptoms of hepatitis or who may be at risk for HBV infection, incorrectly interpreting the assay results as non-reactive assay result, or failing to correctly operate the assay causing a false non-reactive assay result may lead to non-diagnosis or a delay in diagnosis of HBV infection with an associated delay in therapy and potentially increased risk of HBV-related morbidity or mortality. Patients with active infection may unknowingly continue to infect others. False non-reactive results can also lead to unnecessary diagnostic evaluation if alternative etiologies of hepatitis are pursued. False non-reactive assay results may occur if the level of antibody in a specimen is below the limit of detection of the assay.
• A false non-reactive assay result for anti-HBs. When the device is used as an aid in the determination of susceptibility to HBV infection in individuals prior to or following HBV vaccination or where vaccination status is unknown, incorrectly interpreting the assay results as a non-reactive assay result or failing to correctly operate the assay causing a false non-reactive assay result may lead to unnecessary repeated vaccination for HBV.
• A false non-reactive assay result for anti-Hbe. Incorrectly interpreting the assay results as non-reactive assay result or failing to correctly operate the assay causing a false non-reactive assay result may lead to improper patient management, including continued treatment for HBV with antiviral medication. Antiviral medication has risks including toxicity and more rarely allergic reactions. Over time, viral resistance in patients who are co-infected but undiagnosed with other viruses using the same antiviral medication, such as HIV, can lead to viral resistance.

C. Quantitative HBV Nucleic Acid-Based Assays

Decreased assay sensitivity and/or an increased rate of false negative assay reporting may occur with patient samples that contain different genotypes or rare de novo mutations in HBV genomic regions targeted by the device. In these situations, HBV viral load can transiently decrease and/or become undetectable in samples before the virus enters chronic replication.

• A false positive or falsely elevated quantitative HBV nucleic acid assay result. Incorrectly interpreting the assay results as a positive assay result or failing to correctly operate the assay causing a false positive assay result may negatively influence patient management decisions. Such decisions may include the administration or continuation of unnecessary antiviral treatment in patients with chronic HBV infection with its known toxicities and more rarely allergic reactions. Certain patients with falsely elevated HBV nucleic acid assay results may not undergo liver biopsy to investigate other causes of liver disease when the biopsy would otherwise be indicated for certain patients.
• A false negative or falsely decreased quantitative HBV nucleic acid assay result. Incorrectly interpreting the assay results as a negative assay result, or failing to correctly operate the assay causing a false negative assay result may negatively influence patient management decisions for patients with chronic HBV infection, including the withholding of treatment, failure to treat, or premature discontinuation of treating HBV infection when antiviral treatment is otherwise indicated or the choice of an inappropriate treatment. This could lead to adverse effects on patient health such as progressive liver disease, cirrhosis and/or hepatocellular carcinoma, and other cancers. Patients with active HBV replication also risk spreading the virus to others. Certain patients with falsely low HBV nucleic acid assay results may undergo liver biopsy to investigate other causes of liver disease.

VI. Summary of Data Upon Which the Reclassification Is Based

The safety and effectiveness of these device types has become well established since the initial approval of the first qualitative HBV antibody assay in 2000, the first HBV antigen assay in 2001, and the first quantitative HBV nucleic acid-based assay in 2008. FDA has considered and analyzed the following information: (1) accumulated experience regulating these HBV assays, (2) input from the Panel meeting, and (3) postmarket information regarding HBV assays, i.e., information from FDA's publicly available MDR, MAUDE, and Medical Device Recall databases. The available evidence demonstrates that there are public health benefits derived from the use of HBV assays indicated for use to aid in diagnosis of HBV infection and/or for use to aid in the management of HBV infected patients, or as an aid in the determination of susceptibility to HBV infection (anti-HBs). In addition, the nature of the associated risks to health are known, and special controls can be established to sufficiently mitigate these risks.

Based on our review of the information described above, FDA has determined that special controls, in addition to general controls, are necessary to provide a reasonable assurance of safety and effectiveness for HBV assays, and that sufficient information exists to establish such special controls. Therefore, FDA, on its own initiative, is proposing to reclassify these postamendments devices from class III (general controls and premarket approval) into class II (general controls and special controls), subject to premarket notification (510(k)) requirements.

VII. Proposed Special Controls

FDA believes that these devices can be classified into class II with the establishment of special controls. FDA believes that the following proposed special controls would mitigate each of the risks to health described in section V and that these special controls, in addition to general controls, would provide a reasonable assurance of safety and effectiveness for HBV assays. Tables 1 through 3 below demonstrate how FDA believes each risk to health described in section V would be mitigated by the proposed special controls for each device type.

A. Qualitative HBV Antigen Assays

The risk of inaccurate interpretation of assay results can be mitigated by special controls requiring certain labeling, including providing clearly stated warnings and limitations and information on principles of operation and procedures in performing the assay.

Risks associated with false results ( e.g., false non-reactive and false reactive assay results) and with the failure to correctly operate the device can be mitigated through a combination of special controls, including certain labeling requirements, certain design verification and validation information, and performance studies. Examples of verification and validation information to be included in the design of the device include documentation of performance specifications including analytical and clinical performance criteria. In addition, design verification and validation activities must include documentation of a complete device description, critical reagents, risk analysis strategies, lot release criteria, stability studies, and protocols. Required statements in labeling can aid in mitigating the failure of the device to perform as indicated, for example including a statement that use of the assay with specimen types other than those specifically identified for use with this device may cause inaccurate assay results. Special controls requiring additional labeling to provide a brief summary of the instructions for use can also mitigate these risks.