Elecsys Anti-HBs II, PreciControl Anti-HBs, Anti-HBs CalCheck

P190034 · Roche Diagnostics · SEI · Feb 23, 2021 · Microbiology

Device Facts

• Record ID: P190034
• Device Name: Elecsys Anti-HBs II, PreciControl Anti-HBs, Anti-HBs CalCheck
• Applicant: Roche Diagnostics
• Product Code: SEI · Microbiology
• Decision Date: Feb 23, 2021
• Decision: APRL
• Regulation: 21 CFR 866.3173
• Device Class: Class 2
• Attributes: Pediatric

Intended Use

Immunoassay for the in vitro quantitative determination of total antibodies to the hepatitis B surface antigen (HBsAg) in human adult, pregnant women, and pediatric (ages 2 to 21 years) serum and plasma (K₂-EDTA and K₃-EDTA). Assay results may be used as an aid in the determination of susceptibility to hepatitis B virus (HBV) infection for individuals prior to or following HBV vaccination; or where vaccination status is unknown. Assay results may be used with other HBV serological markers for the laboratory diagnosis of HBV disease associated with HBV infection. A reactive assay result will allow a differential diagnosis in individuals displaying signs and symptoms of hepatitis in whom etiology is unknown. The detection of anti-HBs is indicative of laboratory diagnosis of seroconversion from hepatitis B virus (HBV) infection or from vaccination. The electrochemiluminescence immunoassay “ECLIA” is intended for use on the cobas e 601 immunoassay analyzer.

Device Story

Elecsys Anti-HBs II is an in vitro diagnostic immunoassay for quantitative detection of total anti-HBs antibodies in human serum/plasma. Operates on cobas e 601 analyzer using electrochemiluminescence (ECLIA) sandwich format. Input: 40 uL sample; biotinylated HBsAg; ruthenium-labeled HBsAg. Process: two-incubation steps; sandwich complex formation; binding to streptavidin-coated microparticles; magnetic capture on electrode; chemiluminescent emission induced by voltage; measured by photomultiplier. Output: quantitative anti-HBs concentration (mIU/mL) compared against instrument-generated calibration curve. Used in clinical laboratories by trained personnel. Results aid clinicians in assessing HBV immunity, vaccination status, and diagnosing HBV infection. Benefits include improved patient management, reduced transmission, and mitigation of HBV sequelae through timely vaccination or antiviral treatment.

Clinical Evidence

Multi-center clinical study of 4,047 subjects (adults at increased risk, pediatric, pregnant, vaccination cohorts). Compared Elecsys Anti-HBs II against FDA-approved reference assay. Primary endpoints: positive/negative percent agreement (PPA/NPA) by HBV classification. Combined adult AIR cohort (n=2,759) showed 98.6% PPA and 96.5% NPA. Pediatric cohort (n=128) showed 94.8% PPA and 97.1% NPA. Pregnant cohort (n=806) showed 98.6% PPA and 96.8% NPA. Study confirmed analytical equivalence between current and updated (biotin-mitigated) versions.

Technological Characteristics

Quantitative sandwich ECLIA. Reagents: biotinylated HBsAg, ruthenium-labeled HBsAg, streptavidin-coated microparticles. Measuring range: 3.5 to 1000 mIU/mL. Biotin interference mitigation up to 1200 ng/mL. Instrument: cobas e 601. Calibration: 2-point, master curve. Sterilization: N/A (reagents). Connectivity: Integrated with cobas e 601 analyzer.

Indications for Use

Indicated for human adults, pregnant women, and pediatric patients (ages 2-21) to quantitatively detect total anti-HBs antibodies in serum and K2/K3-EDTA plasma. Used to determine HBV susceptibility pre/post-vaccination or when status is unknown, and as an aid in diagnosing HBV infection in symptomatic individuals.

Regulatory Classification

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.

Special Controls

*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.

Reference Devices

• Elecsys Anti-HBs (P010054)

Submission Summary (Full Text)

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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Antibody to Hepatitis B Surface Antigen (Anti-HBs)

Device Trade Name: Elecsys Anti-HBs II
PreciControl Anti-HBs
Anti-HBs CalCheck

Device Procode: LOM

Applicant’s Name and Address: Roche Diagnostics
9115 Hague Road
Indianapolis, IN 36250

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P190034

Date of FDA Notice of Approval: February 23, 2021

## II. INDICATIONS FOR USE

### Elecsys Anti-HBs II

Immunoassay for the in vitro quantitative determination of total antibodies to the hepatitis B surface antigen (HBsAg) in human adult, pregnant women, and pediatric (ages 2 to 21 years) serum and plasma (K₂-EDTA and K₃-EDTA). Assay results may be used as an aid in the determination of susceptibility to hepatitis B virus (HBV) infection for individuals prior to or following HBV vaccination; or where vaccination status is unknown.

Assay results may be used with other HBV serological markers for the laboratory diagnosis of HBV disease associated with HBV infection. A reactive assay result will allow a differential diagnosis in individuals displaying signs and symptoms of hepatitis in whom etiology is unknown. The detection of anti-HBs is indicative of laboratory diagnosis of seroconversion from hepatitis B virus (HBV) infection or from vaccination.

The electrochemiluminescence immunoassay “ECLIA” is intended for use on the cobas e 601 immunoassay analyzer.

### PreciControl Anti-HBs

PreciControl Anti-HBs is used for quality control of the Elecsys Anti-HBs immunoassay on the Elecsys and cobas e immunoassay analyzers and of the Elecsys Anti-HBs II immunoassay on the cobas e 601 immunoassay analyzer. The performance of PreciControl Anti-HBs has not been established with any other anti-HBs assay.

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Anti-HBs CalCheck

Anti-HBs CalCheck is an assayed control material for use in the verification of the calibration established by the Elecsys Anti-HBs immunoassay on the cobas e immunoassay analyzers and by the Elecsys Anti-HBs II immunoassay on the cobas e 601 immunoassay analyzer.

## III. CONTRAINDICATIONS

There are no known contraindications.

## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Elecsys Anti-HBsII labeling.

## V. DEVICE DESCRIPTION

The Elecsys Anti-HBs II is a quantitative serologic, two-incubation step assay using sandwich test format and a total assay time of 18 minutes. In the first incubation, anti-HBs in the sample (40 uL), biotinylated HBsAg (ad/ay), and HBsAg (ad/ay) labeled with ruthenium complex react to form a sandwich complex. In the second incubation, after addition of streptavidin-coated microparticles, the complex becomes bound to the solid phase via interaction of biotin and streptavidin. The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier. Results are determined via a calibration curve which is instrument generated by 2-point calibration and a master curve provided.

## Components

Elecsys Anti-HBs II kit consists of five (5) components as shown in the following table:

Table 1: Components of the Elecsys Anti-HBs II

| Name | Description |
| --- | --- |
| M | Streptavidin-coated microparticles |
| R1 | Biotinylated HBsAg (ad/ay) human and recombinant |
| R2 | HBsAg (ad/ay) human and recombinant, labeled with ruthenium complex |
| Anti HBS II Cal1 | Calibrator 1 Anti-HBs (human) in human serum |
| Anti HBS II Cal2 | Calibrator 2 Anti-HBs (human) in human serum |

The M, R1, and R2 reagents are combined in the "rackpack" (bundle of the three (3) reagent bottles which is placed on the instrument as a single unit)

All reagents, including calibrators, are provided ready for use.

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The Elecsys Anti-HBs II assay is produced in two (2) different package sizes: 100 tests and 200 tests. The two (2) kit sizes differ in the volume of bottles M, R1, and R2. Calibrators 1 and 2 have the same filling volume.

The 100-test kit of the Elecsys Anti-HBs II is defined as the master kit. All studies will be performed with the master kit, as study results from the master kit are considered to be transferable to the 200-test kit.

The PreciControl Anti-HBs consists of two (2) reagents:
- PC A-HBS1: PreciControl Anti-HBs 1, human serum, negative for anti-HBs
- PC A-HBS2: PreciControl Anti-HBs 2, human serum, positive for anti-HBs, approx. 100 IU/L

The Anti-HBs CalCheck is an assay control material for use in the verification of the calibration established by the Elecsys Anti-HBs immunoassay and is FDA approved (P010054). This material remains unchanged. It consists of three (3) reagent components (three (3) bottles, one of each level negative, mid level, and high level of anti-HBs).

## Interpretation of Results

The accepted criterion for immunity to HBV is $\geq 10\mathrm{mIU/mL}$ of anti-HBs, with mIU defined by the World Health Organization (WHO) Reference Preparation.

Table 2: Interpretation of Results
| Elecsys Anti-HBs II result | Result interpretation | Clinical interpretation of HBV immune status |
| --- | --- | --- |
| < 10 mIU/mL | Non-reactive | Individual is considered to be not immune to infection with HBV. |
| ≥ 10 mIU/mL | Reactive | Anti-HBs concentration detected at > 10 mIU/mL. Individual is considered to be immune to infection with HBV. |

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the detection and quantitation of antibodies to hepatitis B surface antigen (Anti-HBs). There are currently several FDA approved in invitro diagnostic tests commercially available for serological markers of hepatitis B virus (HBV) which, when used in conjunction with a patient's medical history, clinical examination and other laboratory findings, may be 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. The assay may be 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. Each alternative has its own advantages and disadvantages. A patient

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should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

Elecsys Anti-HBs II and PreciControl Anti-HBs are currently marketed globally in several countries. The device has not been withdrawn to date from the market in any country for reasons relating to safety and effectiveness of the device.

Table 3: Countries Where Elecsys Anti-HBs II is Currently Marketed (100-test kit size)

| Australia | El Salvador | Korea (the Republic of) | Singapore |
| --- | --- | --- | --- |
| Brazil | European Union | Myanmar | Taiwan, Republic of China |
| Canada | Guatemala | Nicaragua | Thailand |
| China | Honduras | Panama | Turkey |
| Colombia | India | Peru | Uruguay |
| Costa Rica | Indonesia | Philippines (the) | Venezuela, Bolivarian Republic of |
| Cuba | Iran (the Islamic Republic of) | Poland | Vietnam |
| Ecuador | Japan | Saudi Arabia (kingdom of) | |

Table 4: Countries Where Elecsys Anti-HBs II is Currently Marketed (200-test kit size)

| Australia | Cuba | Japan | Saudi Arabia (Kingdom of) |
| --- | --- | --- | --- |
| Brazil | Ecuador | Korea (the Republic of) | Singapore |
| Canada | El Salvador | Myanmar | Taiwan, Republic of China |
| China | European Union | Panama | Thailand |
| Colombia | Guatemala | Peru | Turkey |
| Costa Rica | India | Poland | Vietnam |

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device. The Elecsys Anti-HBs II is intended for in vitro diagnostic use, and as a result, there is no direct adverse effect on the patient. Standard good laboratory practices are considered sufficient to minimize risks to the end user.

Failure of the product to perform as intended or human error in the use of this test may lead to a false result. Appropriate Warnings and Precautions for identified risks are contained in the labeling and assay Instructions for Use.

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The risks associated with the device, when used as intended, are those related to the risk of false test results, failure to correctly interpret the test results, and failure to correctly operate the device.

Risks of false positive results when the device is used as an aid in the diagnosis of hepatitis B virus (HBV) infection in patients with symptoms of hepatitis or who may be at risk for HBV infection include improper patient management, including treatment for hepatitis B with antiviral medication. Antiviral medication has risks including toxicity and more rarely allergic reactions. Over time, viral resistance in patients who are coinfected but undiagnosed with other viruses that are treated with the same antiviral medication, such as HIV, can lead to viral resistance, however the chance of an undiagnosed co-infection in a patient treated for hepatitis B is unlikely.

Risks of false positive results 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 includes leading a provider to falsely believe that a patient has been vaccinated in the past and/or has current immunity when the patient, in fact, does not. This could lead to a missed opportunity to vaccinate a patient in whom Hepatitis B vaccination is indicated. Vaccination for appropriate patients can mitigate the sequelae of hepatitis B infection and may result in improved morbidity and mortality in these patients. Known sequelae of hepatitis B infection include continued symptoms, increases in all-cause mortality, liver disease-related complications and death, hepatocellular carcinoma rates, and need for liver transplantation. Vaccination for hepatitis B infection can potentially decrease transmission and disease burden in the general population and particularly in populations at high risk for hepatitis B infection.

Risks of false negative results 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 include potentially missing and not treating a patient who has hepatitis B infection. Missing and not treating a patient with hepatitis B infection whose clinical picture warrants antiviral treatment could result in the known sequelae of HBV infection and may result in high morbidity and mortality in these patients. Additionally, missing a diagnosis of hepatitis B infection will not allow for clinicians to potentially decrease transmission and disease burden in the general population, particularly in populations at high risk for hepatitis B infection.

Risks of false negative results 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 include unnecessary repeated vaccination for hepatitis B. Although vaccination has risks such as local reactions, and serious adverse events due to Hepatitis B vaccination are rare, administration of extra doses of single-antigen hepatitis B vaccine is not generally harmful. In fact, it is common practice to administer higher dose vaccinations in an accelerated schedule for patients undergoing organ transplantation, for example.

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IX. SUMMARY OF NONCLINICAL STUDIES

Note that the following units are equivalent and are used interchangeably IU/L = mIU/mL.

A. Laboratory Studies

Roche Diagnostics launched the Elecsys Anti-HBs II system globally with a biotin interference at a level of 8 ng/mL. Roche decided to update the assay by addition of a biotin scavenger antibody which increased the level for biotin interference up to 1200 ng/mL. As Roche had already performed the clinical studies, Roche performed bridging studies (See Part II below) to show analytical equivalence between the “current” Elecsys Anti-HBs II and the “updated” Elecsys Anti-HBs II that included the biotin remediation. Only the “updated” Elecsys Anti-HBs II will be sold in the US. The following section describes the analytical studies with the current and the updated versions of the Elecsys Anti-HBs II.

Part I. Non-Clinical Studies with the Current Elecsys Anti-HBs II

1. Equivalency Studies Between 100 and 200 test kits (studies with an asterisk “*” are not presented in the Package Insert)

a. Comparison study* was conducted to determine the equivalency of 100 and 200 test kits when the rackpack contents are full and as the contents are depleted. Five (5) human serum pools were tested with full and almost used up rackpacks on two (2) cobas e 601 analyzers. Each sample was measured in 21 replicates. The results show that the sample concentrations are similar when tested with 100 and 200 test kit when it is either full or depleted.

b. Reagent Temperature Stress (Transport Stability)* was conducted to determine the effect of elevated temperature on Elecsys Anti-HBs II. The 100 and 200 test kit configurations including calibrators were stored for one week at 35°C (stressed condition). Five (5) human serum pools and both controls were tested in duplicate with the stressed and unstressed (stored at 2-8°C) reagent kit. Testing was performed on one day with one analyzer. The mean recovery of the samples was calculated based on the mean of the reference. The results were similar between the stressed and unstressed kit.

c. Reagent On-Board Stability-Open Reagent Pack Stability* was assessed by storing 100 and 200 test kit configurations on-board the cobas e 601 for 9 weeks at 20°C ± 3°C. After 1, 2, 3, 4, 5, 6, 7, 8, and 9 weeks, five (5) human serum pools were measured with regard to stability of the weekly calibration. Unstressed reagent packs of both 100 and 200 test kits (stored at 2-8°C) were opened and calibrated. Recovery of the mean value of each sample was calculated comparing to the mean value of the unstressed reagent pack at day 0. The stability of the current Elecsys Anti-HBs II meets the acceptance criteria

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for 9 weeks and supports a claim for storage of 8 weeks on-board the cobas e 601 analyzer.

d. Reagent After First Opening Stability* was performed to determine the time period in which the reagents can be kept at 2-8°C once opened. New reagent packs 100 and 200 test kit configuration were opened and two (2) of them stored at 2-8°C for 8 and 9 weeks. One opened, new reagent pack (unstressed reference was calibrated). Five (5) human serum pools and the PreciControls were tested in duplicate at time point 0. After 8 and 9 weeks, the samples were tested again in duplicate with the stressed reagent packs stored after first opening at 2-8°C. Reagent pack stability was determined by calculating the mean recovery of the samples compared to the mean of the unstressed reference.

2. Precision*

A precision panel consisting of seven (7) native human serum samples or serum pools (HS) and two (2) PreciControls were measured. The samples were either low (2 samples ≤5 IU/L), medium (1 sample &gt;5 to ≤10 IU/L), and high (4 samples &gt;10 IU/L with one sample just above 10 IU/L). Each sample was separated into two (2) aliquots. These aliquots were measured in single determinations in two (2) runs per day (n=4 per day) and in total 12 days (n=48). The measurements were performed on one cobas e 601 analyzer at one site with one reagent lot spanning two (2) calibration cycles. Repeatability and within-laboratory precision were calculated according to CLSI EP05-A3. The results met the acceptance criteria and are shown in the following table.

Table 5: Precision Results
| | | Repeatabilitya | | Intermediate Precisionb | |
| --- | --- | --- | --- | --- | --- |
| Sample | Mean mIU/mL | SDc mIU/mL | %CV | SD mIU/mL | %CV |
| Human serum 1 | 0.786 | 0.253 | 32.2 | 0.280 | 35.7 |
| Human serum 2 | 3.36 | 0.245 | 7.3 | 0.278 | 8.3 |
| Human serum 3 | 8.68 | 0.250 | 2.9 | 0.316 | 3.6 |
| Human serum 4 | 10.2 | 0.303 | 3.0 | 0.327 | 3.2 |
| Human serum 5 | 76.7 | 1.79 | 2.3 | 2.26 | 3.0 |
| Human serum 6 | 508 | 7.19 | 1.49 | 11.1 | 2.2 |
| Human serum 7 | 800 | 7.00 | 0.9 | 15.7 | 2.0 |
| PC1 | 0 | - | - | - | - |
| PC2 | 82.2 | 0.813 | 1.0 | 1.87 | 2.3 |

aRepeatability = within-run precision
bIntermediate precision = within-laboratory precision
cStandard Deviation

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3. Determination of limit of blank (LoB) and limit of detection (LoD)

The LoB and LoD were determined in accordance with CLSI EP17-A2. For determination of LoB, five (5) commercially sources analyte-free human serum pools were measured with two (2) reagent lots in single determination on three (3) days with two (2) runs per day on two (2) cobas e 601 analyzers. For each lot in ototal 60 measured values of analyte-free samples were obtained (2 runs x 3 days x 2 analyzers x 5 samples). Data analysis was based on determination of the 95th percentile of the 60 measured values. The results show that LoB=0 for both lots tested.

For determination of LoD, five (5) human serum pools with low analyte concentration were measured in two (2) lots in single determination over three (3) days with two (2) runs per day on two (2) cobas e 601 analyzers. For each lot in total 60 measured values of samples with low analyte concentration were obtained (2 runs per day x 3 days x 3 analyzers x 5 samples). Data analysis was based on determination of the 60 measured values as follows:

$$
\mathrm{LoD} = \mathrm{LoB} + 1.653 \times \mathrm{SD} \text{ total where SD total} = \text{square root of } [0.2 \left\{ (\mathrm{sd}1)2 + \ldots + (\mathrm{sd}5)2 \right\} ]
$$

The LoD for lot 1 is 0.4513 IU/L and for lot 2 is 0.3994 IU/L.

The claimed LoB is 1.5 mIU/mL and the claimed LoD is 2 mIU/mL.

4. Limit of Quantitation (LoQ)

The LoQ was determined in accordance with CLSI EP17-A2. Eight (8) commercially sourced human serum pools covering the concentration range from LoB to 2xLoQ were measured in five-fold determinations in five (5) runs with one run per day. LoQ is defined as the mean value of the samples which fulfills specifications for the intermediate precision (CV) and for which no sample with higher concentration exists that exceeds this specification. LoQ was determined to be 1.48 mIU/mL. The claimed LoQ is 3.5 mIU/mL

5. Linearity

Three (3) native human serum and plasma samples with analyte content were diluted down to the lower end of the measuring range with various amounts of low analyte human sample. Twelve (12) dilution steps were completed and each dilution series was tested in triplicate. The linearity data was analyzed with regards to linear, quadratic and cubic polynomials according to CLSI EP06-A. Linearity for the Elecsys Anti-HBs II is from 0 to 1177 IU/L in serum and 0 to 1140 IU/mL in plasma. The claimed measuring range is 3.5 to 1000 mIU/mL.

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# 6. High Dose Hook Effect

Three (3) native human serum samples were diluted in at least 11 dilution steps to generate dilution series that covers the measuring range from negative to high positive concentration. The diluted samples were measured in three-fold determination. Although a decrease in signal in samples &gt;20,000 mIU/mL was observed, the samples still produced a positive signal. The high dose hook effect did not lead to false negative results in the assay. Due to high-dose hook effect, results from anti-HBs concentrations with samples &gt;1000 mIU/mL to 500,000 mIU/mL were properly detected as ≥100 mIU/mL.

# 7. Endogenous Interference

Several potential endogenous interferents were tested using both native or spiked serum samples. Dilution series with at least nine (9) dilution steps each were prepared for serum samples for all interfering substances by diluting samples spiked with a high concentration of the interfering substance with the corresponding unspiked sample. Samples were tested in duplicate. Mean recovery values of samples spiked with interfering substance were calculated against the respective sample without the interfering substance. No interference was observed for the tested concentrations below.

Table 6: Endogenous Interference

| Compound | Concentration Tested |
| --- | --- |
| Hemoglobin | ≤1g/dL |
| Bilirubin | ≤30 mg/dL |
| Intralipid® (Lipemia) | ≤1500 mg/dL |
| Biotin | ≤1200 ng/mL |
| Human Serum Albumin | ≤7.0 g/dL |
| Rheumatoid Factor | ≤1200 IU/mL |
| IgG | ≤7.0 g/dL |
| IgM | ≤1.0 g/dL |
| IgA | ≤1.6 g/dL |

# 8. Analytical Specificity/Cross-Reactivity

Analytical specificity with medical conditions and diseases with similar etiology or symptoms to hepatitis B viral infection was tested on 96 samples. These samples were not prescreened for the presence of anti-HBs. Testing with the reference assay shows that these samples were positive for anti-HBs. The presence of potential interferent did not change the reactive result (there were no false negatives observed) with the Elecsys Anti-HBs II assay. The results are shown in the table below.

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Table 7: Reactivity of the Elecsys Anti-HBsII Assay in Individuals with Various Medical Conditions

| | | Elecsys Anti- HBs II | | |
| --- | --- | --- | --- | --- |
| Category | Subcategory | RXa) | NRb) | Total |
| Immune disorders | ANA | 3 | 0 | 3 |
| | RF | 1 | 0 | 1 |
| | SLE | 1 | 0 | 1 |
| Infections/ disorders | T. pallidum | 5 | 0 | 5 |
| | Toxoplasmosis | 9 | 0 | 9 |
| Infectious viral | CMV | 8 | 0 | 8 |
| | EBV | 5 | 0 | 5 |
| | HAV | 6 | 0 | 6 |
| | HCV | 2 | 0 | 2 |
| | HIV | 6 | 0 | 6 |
| | HSV | 9 | 0 | 9 |
| | HTLV | 4 | 0 | 4 |
| | Parvo B19 | 7 | 0 | 7 |
| | Rubella | 10 | 0 | 10 |
| | VZV | 6 | 0 | 6 |
| Non-viral liver disease | Alcohol liver disease | 2 | 0 | 2 |
| | Other non-viral liver disease | 5 | 0 | 5 |
| | Primary biliary cirrhosis | 1 | 0 | 1 |
| Vaccination | Influenza | 6 | 0 | 6 |
| Total | | 96 | 0 | 96 |

a) RX = reactive
b) NR = non-reactive

For evaluation of cross-reactivity, a total of 187 negative anti-HBs samples tested by the reference method were tested for potentially cross-reactive medical conditions or diseases with similar etiology or symptoms to hepatitis B viral infection using the Elecsys Anti-HBs II assay. The following percent of cross-reactivity was observed: SLE 9%, EBV 10%, HCV 9%, HEV 5%, Rubella 20%, VZV 11%.

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Table 8: Reactivity of the Elecsys Anti-HBsII Assay in Individuals with Various Medical Conditions

| | | Elecsys Anti-HBs II | | |
| --- | --- | --- | --- | --- |
| Category | Subcategory | RXa) | NRb) | Total |
| Immune disorders | ANA | 0 | 12 | 12 |
| | RF | 0 | 14 | 14 |
| | SLE | 1 | 10 | 11 |
| Infections/disorders | T. pallidum | 0 | 10 | 10 |
| | Toxoplasmosis | 0 | 6 | 6 |
| Infectious viral | CMV | 0 | 7 | 7 |
| | EBV | 1 | 9 | 10 |
| | HAV | 0 | 4 | 4 |
| | HCV | 1 | 10 | 11 |
| | HEV | 1 | 18 | 19 |
| | HIV | 0 | 9 | 9 |
| | HSV | 0 | 6 | 6 |
| | HTLV | 0 | 10 | 10 |
| | Parvo B19 | 0 | 8 | 8 |
| | Rubella | 1 | 4 | 5 |
| | VZV | 1 | 8 | 9 |
| Non-viral liver disease | Alcohol liver disease | 0 | 4 | 4 |
| | Other non-viral liver disease | 0 | 2 | 2 |
| | Primary biliary cirrhosis | 0 | 26 | 26 |
| Vaccination | Influenza | 0 | 4 | 4 |
| Total | | 6 | 181 | 187 |

a) RX=reactive
b) NR=non-reactive

9. Serum/Plasma Comparison*

This study was conducted to examine suitability of the following kinds of blood collection sample types for the current Elecsys Anti-HBs II:

- Serum sample tubes including separating gel tubes
- Potassium EDTA (K2EDTA) plasma including separating gel tubes
- Potassium EDTA (K3EDTA) plasma

Serum gel separation tubes, K2EDTA, K3EDTA plasma: native sample pairs were collected into serum and plasma collection sample types and assayed in either duplicate (serum) or single determination (plasma, serum separation tubes) using current Elecsys Anti-HBs II on the cobas e 601 analyzer.

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K2EDTA plasma separating gel tubes: native plasma pairs were collected into plasma (=control) and plasma separating tubes and assayed in duplicate determination. Results are shown in the following tables.

Table 9: Serum Plasma Comparison Absolute Percentage Bias Relative to Serum

| Tube Type | Distribution of absolute percentage difference relative to serum | | |
| --- | --- | --- | --- |
| | < 10% | ≥ 10% to ≤ 20% | > 20% |
| Serum Gel Separation | 96.7% (59/61) | 1.64% (1/61) | 1.64% (1/61) |
| K2EDTA | 80.3% (49/61) | 13.1% (8/61) | 6.5% (4/61) |
| K2EDTA Gel Separation | 96.2% (51/53) | 3.8% (2/53) | 0% (0/53) |
| K3EDTA | 67.2% (41/61) | 29.5% (18/61) | 3.27% (2/61) |

Table 10: Serum Plasma Comparison Statistical Evaluation

| | Serum separation tubes | K2EDTA Plasma | K2EDTA Gel Separation Plasma | K3EDTA Plasma |
| --- | --- | --- | --- | --- |
| Sample size normally filled tubes | 61 | 61 | 53 | 61 |
| Slope (BaPa) | 0.991 | 0.948 | 1.000 | 0.912 |
| Intercept (BaPa) | 0.000 | 0.000 | 0.070 | 0.000 |
| Correlation (Pearson) | 1.00 | 0.997 | 1.000 | 0.999 |
| Bias at medical decision point | -0.9%; (-1.7%/-0.1%) | -5.2%; (-6.8%/-4.3%) | 0.7%; (-3.4%/5.8%) | -8.8%; (-10.0%/-8.1%) |

10. Drug Interference

Seventeen (17) common therapeutic drugs and 10 special drugs were tested for potential interference. The drug spiked serum samples were evaluated at a concentration C1 ("x" times the maximum daily dosage). No interference was observed with the following compounds.

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Table 11: Drug Interference

| Compound | Concentration [mg/L] |
| --- | --- |
| Acetylcysteine | 150 |
| Ampicillin-Na | 1000 |
| Ascorbic acid | 300 |
| Cyclosporine | 5 |
| Cefoxitin | 2500 |
| Heparin | 5000 U/L |
| Intralipid | 10,000 |
| Levodopa | 20 |
| Methyldopa | 20 |
| Metronidazole | 200 |
| Phenylbutazone | 400 |
| Doxycyclin | 50 |
| Acetylsalicylic acid | 1000 |

# 11. Seroconversion

Seroconversion sensitivity was evaluated by testing 11 commercially available seroconversion panels and comparing the Elecsys Anti-HBs II assay with the reference assay. Results show that seven (7) panels demonstrated conversion of negative/non-reactive to positive/reactive. Performance in five (5) panels was equivalent between the Elecsys Anti-HBs II and the reference assay, while the Elecsys Anti-HBs II showed seroconversion to reactive one draw later than the reference assay in two (2) panels. The following table shows the results. Two (2) panels did not show seroconversion.

Table 12: Seroconversion Sensitivity

| | Elecsys Anti-HBs | | Elecsys Anti-HBs II | | |
| --- | --- | --- | --- | --- | --- |
| Panel ID | negative | positive | non-reactive | reactive | |
| Initially negative/non-reactive, converted to positive/reactive | | | | | Difference in Days to Elecsys Anti-HBs II Reactivity (Reference-Test) |
| 6281 | 43 | 50 | 43 | 50 | 0 |
| 6506 | 41 | 55 | 55 | 69 | +14 |
| 6508 | 70 | 84 | 70 | 84 | 0 |
| 6510 | 70 | 84 | 70 | 84 | 0 |
| 6529 | 42 | 56 | 42 | 56 | 0 |
| 6534 | 14 | 29 | 29 | 43 | +14 |
| PHM935Ba | 231 | 262 | 246 | 262 | 0 |

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| Initially positive/reactive, converted to negative/non-reactive | | | | | Difference in Days of Sustained Initial Reactivity (Test-Reference) |
| --- | --- | --- | --- | --- | --- |
| 6272 | 108 | 104 | 104 | 101 | -3 |
| 11000^{b} | 26 | 19 | 21 | 19 | 0 |
| Negative/non-reactive throughout series | | | | | |
| 9092 | 198 | - | 198 | - | No seroconversion |
| RP-017 | 188 | - | 188 | - | No seroconversion |

a) Elecsys Anti-HBs II was negative on day 246, while Elecsys Anti-HBs was indeterminate on day 246
b) Elecsys Anti-HBs II was negative on day 21, while Elecsys Anti-HBs was indeterminate

## 12. Carryover Study*

On the cobas e 601 analyzer, the use of disposable tips for sample pipetting eliminates any risk of sample carry over by design. An Anti-HBs negative sample was tested in triplicate followed by a high-signal-generating-sample (≥2 Mio counts) of another Elecsys assay (Toxo IgG immunoassay) was tested followed again by the anti-HBs negative samples tested with the Elecsys Anti-HBs II in triplicate.

All acceptance criteria were met, demonstrating that no significant amount of analyte is carried over from one sample reaction into the subsequent sample reactions.

## 13. Reproducibility

Reproducibility was determined with a panel of six (6) human sera and two (2) controls. Samples were measured in triplicate using three (3) reagent lots, in two (2) runs per day for five (5) days at three (3) sites according to CLSI EP15-A2 and CLSI EP05-A3 (n=180). Variance components were calculated absolutely, as well as in relative contribution to total size variance. The following table shows the results.

Table 13: Reproducibility

| | | | Repeatability | | Between-run | | Between-day | | Between-lot | | Between-lab | | Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Sample | N | Mean mIU/mL | SD, mIU/mL | % CV | SD, mIU/mL | % CV | SD, mIU/mL | % CV | SD, mIU/mL | % CV | SD, mIU/mL | % CV | SD, mIU/mL | % CV |
| HSP 01 | 180 | 8.87 | 0.252 | 2.85 | 0.171 | 1.93 | 0.048 | 0.55 | 0.478 | 5.39 | 0.000 | 0.00 | 0.569 | 6.42 |
| HSP 06 | 180 | 9.85 | 0.268 | 2.72 | 0.980 | 0.99 | 0.193 | 1.96 | 0.729 | 7.40 | 0.000 | 0.00 | 0.806 | 8.18 |
| HSP 02 | 180 | 11.22 | 0.279 | 2.49 | 0.191 | 1.70 | 0.124 | 1.11 | 0.704 | 6.28 | 0.000 | 0.00 | 0.791 | 7.05 |
| HSP 05 | 180 | 77.35 | 1.11 | 1.44 | 0.794 | 1.03 | 0.778 | 1.01 | 1.86 | 2.40 | 2.32 | 3.00 | 3.36 | 4.35 |
| HSP 03 | 180 | 379.6 | 4.33 | 1.14 | 4.78 | 1.26 | 3.21 | 0.85 | 12.46 | 3.28 | 0.000 | 0.00 | 14.40 | 3.79 |
| HSP 04 | 180 | 823.8 | 10.90 | 1.32 | 9.33 | 1.13 | 6.26 | 0.76 | 15.46 | 1.88 | 23.52 | 2.86 | 32.21 | 3.91 |
| PC A-HBS-1 | 180 | 0.002 | 0.029 | 1341 | 0.000 | 0.00 | 0.000 | 0.00 | 0.000 | 0.00 | 0.000 | 0.00 | 0.029 | 1342 |

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| | | | Repeatability | | Between-run | | Between-day | | Between-lot | | Between-lab | | Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Sample | N | Mean mIU/mL | SD, mIU/mL | % CV | SD, mIU/mL | % CV | SD, mIU/mL | % CV | SD, mIU/mL | % CV | SD, mIU/mL | % CV | SD, mIU/mL | % CV |
| PC A-HBS-2 | 180 | 95.61 | 1.20 | 1.26 | 1.51 | 1.58 | 0.437 | 0.46 | 1.65 | 1.73 | 2.89 | 3.03 | 3.88 | 4.05 |

## 14. Sample Stability

Four (4) studies were conducted to verify stability of patient serum and plasma samples.

i) Storage at 2-8°C. Eleven (11) native serum and plasma samples were measured in triplicate unstressed (fresh) and after storage for 1, 2, 6, and 7 days at 2-8°C. Results confirm storage of samples at 2-8°C for 6 days.
ii) Storage at -20°C. Eleven (11) native serum and plasma samples were measured in triplicate unstressed and after storage for 1, 2, 3, and 4 months at -20°C. Results confirm storage of samples at -20°C for up to 4 months.
iii) Storage at 25°C. Eleven (11) native serum and plasma samples were measured in triplicate unstressed and after storage for 1 and 4 days at 20-25°C. Results confirm storage of samples at 20-25°C for up to 4 days.
iv) Freeze/that Cycles. Eleven native serum and plasma samples were measured in triplicate unstressed and after 2, 5, and 6 freeze/thaw cycles. Results confirm samples may undergo a maximum of 6 freeze/thaw cycles prior to testing.

## 15. Calibration Stability

Calibration must be performed once per reagent lot using the Elecsys Anti-HBs II Cal1, Cal2, and fresh reagent (i.e., no more than 24 hours since the reagent kit was registered on the analyzer). Renewed calibration is recommended as follows:

- After 1 month (28 days) when using the same reagent lot
- After 7 days (when using the same reagent kit on the analyzer)
- As required (e.g., quality control findings with PreciControl Anti-HBs outside the specified limits).

When a reagent lot is first calibrated, the cobas e 601 analyzer will generate a "Lot Calibration" (as long as the reagent pack was not stored on-board the analyzer for more than 24 hours prior to calibration). A lot calibration can be used with multiple reagent packs of the same lot for a one-month period. If an individual reagent pack is on-board the system for more than 7 days, a recalibration must be performed. Two (2) studies were designed to support calibration frequency claims

## Study 1: Lot Calibration Stability

The initial calibration was done with unstressed/fresh reagent at time point 0. Fresh reagent of the same lot was run after 29 days again using initial calibration to

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demonstrate stability of initial calibration. Five (5) human serum pools and PreciControl (PC1 and PC2) were tested in duplicate at time point 0 (unstressed reference) and again after 29 days using the initial calibration but fresh reagent from the same lot on three (3) different analyzers. Results support 28 days of lot calibration stability.

## Study 2: On-Board Calibration Stability

A new reagent pack of the current Elecsys Anti-HBs II was opened and calibrated, unstressed and after storage on-board the cobas e 601 analyzer for one week, with regard to stability of the weekly calibration. A new reagent pack was opened and calibrated. Five (5) human serum pools and the PreciControl were tested in duplicate with fresh reagent pack after initial calibration (timepoint 0=unstressed) and again after 8 days on-board storage (20°C ± 3°C) of the reagent pack using the initial calibration. Results support calibration stability for 7 days on-board cobas e 601 analyzer.

## 16. Calibrator Stability After First Opening

Study was performed to determine time period in which current Elecsys Anti-HBs II calibrators can be kept at 2-8°C once opened. A new reagent pack and calibrator vials were opened and closed. After 8 and 9 weeks storage at 2-8°C, the calibrator counts of the once opened calibrators were tested in duplicate together with unopened (=unstressed) calibrator. Calibrator stability was determined by calculation of the recovery of the calibrator signals (counts) of opened calibrators compared to unstressed calibrator signals (counts). Results support calibrator stability for 8 weeks at 2-8°C.

## 17. On-Board Stability-Open Calibrators

A current Elecsys Anti-HBs II reagent pack was opened and calibrator counts determined (unstressed) in duplicate. Reagent pack was stored at 2-8°C, and the opened calibrators stored at 20-25°C to simulate on-board stress. The stressed calibrators were tested after 6 hours in duplicate. Results support stability of calibrators for 6 hours on-board the cobas e 601 analyzer.

## Part II. Non-Clinical Briding Studies with Updated Elecsys Anti-HBs II

The following studies were performed as bridging studies to support equivalency between the "current" Elecsys HBs II without biotin mitigation and the "updated" Elecsys Anti-HBs II with biotin mitigation.

## 1. Precision

Precision was determined on the cobas e 601 analyzer using Elecsys reagents and controls in a protocol (EP05-A3) of the CLSI (Clinical and Laboratory Standards Institute). Results were generated from an 8 member panel and 2 controls, assayed

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in 2 runs per day in duplicate each for 12 days (n = 48). The following results were obtained:

Table 14: Precision Repeatability Results
| | | Repeatabilitya | | Intermediate precisionb | |
| --- | --- | --- | --- | --- | --- |
| Samplec | Mean mIU/mL | SD mIU/mL | CV % | SD mIU/mL | CV % |
| Human serum 1 | 3.94 | 0.410 | 10.4 | 0.462 | 11.7 |
| Human serum 2 | 8.57 | 0.384 | 4.5 | 0.587 | 6.8 |
| Human serum 3 | 10.8 | 0.373 | 3.5 | 0.535 | 5.0 |
| Human serum 4 | 100 | 2.10 | 2.1 | 3.20 | 3.2 |
| Human serum 5 | 12.2 | 0.455 | 3.7 | 0.686 | 5.6 |
| Human serum 6 | 13.1 | 0.303 | 2.3 | 0.580 | 4.4 |
| Human serum 7 | 577 | 11.2 | 1.9 | 19.1 | 3.3 |
| Human serum 8 | 949 | 14.3 | 1.5 | 31.1 | 3.3 |
| PreciControl A-HBS1 | 0.239 | 0.616 | 258 | 0.986 | 413 |
| PreciControl A-HBS2 | 107 | 1.58 | 1.5 | 3.71 | 3.5 |

aRepeatability = within-run precision
bIntermediate precision = within-laboratory precision
cOne human serum pool member was excluded as mean recovery was 1.15 mIU/mL

2. Reproducibility*

Reproducibility panel consisting of four (4) human serum pools (below- around- and above the medical decision point and in the upper half of the measuring range) and PreciControls were measured in triplicate determinations in two (2) runs per day for 5 days on the same instrument at three (3) different sites (one internal and two (2) external sites) on one cobas e 601 analyzer at each site spanning two (2) calibration cycles. Repeatability and intermediate precision were calculated according to CLSI EP05-A3.

The following table shows the results. Results met acceptance criteria.

Table 15: Reproducibility Results
| | Sample | | PC2 | HSP 01 | HSP 02 | HSP 03 | HSP 04 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Mean | [IU/L] | | 113 | 1.31 | 11.8 | 97.7 | 556 |
| Repeatability | SD | [IU/L] | 1.94 | 0.298 | 0.506 | 176 | 10.6 |
| | CV | [%] | 171 | 22.8 | 4.27 | 1.80 | 1.90 |
| | SD | [IU/L] | 2.81 | 0.394 | 0.000 | 2.07 | 14.4 |

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| Between-Run | CV | [%] | 2.48 | 30.1 | 000 | 2.12 | 2.59 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Between-Day | SD | [IU/L] | 2.63 | 0.000 | 0.415 | 2.57 | 12.0 |
| | CV | [%] | 2.32 | 0.00 | 3.50 | 2.63 | 2.15 |
| Intermediate Precision | SD | [IU/L] | 4.30 | 0.494 | 0.655 | 3.74 | 21.5 |
| | CV | [%] | 3.81 | 37.8 | 5.53 | 3.83 | 3.87 |
| Between-Site | SD | [IU/L] | 16.8 | 0.000 | 0.471 | 4.54 | 29.3 |
| | CV | [%] | 14.9 | 0.00 | 3.97 | 4.65 | 5.28 |
| Reproducibility | SD | [IU/L] | 17.3 | 0.494 | 0.806 | 5.88 | 36.4 |
| | CV | [%] | 15.3 | 37.8 | 6.81 | 6.02 | 6.54 |

# 3. Comparison Study*

A comparison study was performed to show equivalency between the performance of the updated Elecsys Anti-HBs II assay and the current Elecsys Anti-HBs II assay on the cobas e 601 analyzer. A total of 541 native serum samples commercially sourced were measured internally with three (3) different reagent lots of each assay in single determination. The median of the values measured with the current Elecsys Anti-HBs II assay was taken as reference and used for comparison to the values generated with each of three (3) different lots of updated Elecsys Anti-HBs II.

The following table shows the concentration ranges of the samples.

Table 16: Method Comparison Study Sample Concentrations

| Concentration [IU/L] | N (based on median value obtained with three lots of the current Elecsys Anti-HBs II) |
| --- | --- |
| Below the medical decision point: 3.5 ≤ x < 5 | 130 |
| Around medical decision point: 5 ≤ x < 15 | 64 |
| Above the medical decision point: 15 ≤ x < 500 | 300 |
| In the upper half of the measuring range: 500 ≤ x < 1000 | 47 |

Evaluation of Method Comparison Study was performed as follows:

- Method Comparison with scatter plot and descriptive statistics provided separately as well as combined for all system configurations.
- Bias calculated using Passing/Bablok and Weighted Deming regression analysis

The following tables show the overall/combined results.

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Table 17: Overall Results Updated Elecsys Anti-HBs II versus Current Elecsys HBs II Across All 3 Lots

| | Passing/Bablok | Weighted Deming |
| --- | --- | --- |
| N | 541 | |
| Range | 3.50 – 976 IU/L | |
| Slope | 1.03 | 1.01 |
| 95% LCL | 1.02 | 0.996 |
| 95% UCL | 1.05 | 1.03 |
| Intercept | -0.115 | -0.275 |
| 95% LCL | -0.172 | -0.357 |
| 95% UCL | -0.060 | -0.193 |
| Correlation Coefficient | Kendall`s τ= 0.957 | Pearson`s r= 0.992 |
| Bias at Medical Decision Point (10 IU/L) | | |
| Absolute Bias | 0.213 | -0.170 |
| 95% LCL (IU/L) | 0.090 | -0.292 |
| 95% UCL (IU/L) | 0.308 | -0.048 |

Table 18: Regression Plot For All Samples Across Measuring Range

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Table 19: Regression Plot For Samples Near Medical Decision Point

Table 20: Bland Altman Plot (Absolute Difference)

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Table 21: Bland Altman Plot (Relative Difference)

Table 22: Agreement Rates and Two-Sided $95\%$ Confidence Intervals (CI)

| Updated Elecsys Anti-HBs II* | Current Elecsys Anti-HBs II* | | |
| --- | --- | --- | --- |
| | Non-reactive | Reactive | Total |
| Non-reactive | 180 | 7 | 187 |
| Reactive | 0 | 354 | 354 |
| Total | 180 | 361 | 541 |
| | | | |
| Negative Percent Agreement | 100% (180/180) 95% CI: 97.91-100% | | |
| Positive Percent Agreement | 98.06% (354/361) 95% CI: 96.05-99.06% | | |

*The median results of the three (3) lots were used to determine non-reactive and reactive status and are presented here.

Method Comparison between current and updated Elecsys Anti-HBs II assays on the cobas e 601 analyzer show equivalent results where there was no statistically significant systematic different between the two (2) systems and $&gt;95\%$ of the sample results fall within allowable total difference (ATD) zones.

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# X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness for the detection of antibodies to hepatitis B surface antigen with the current Elecsys Anti-HBs II using samples that would routinely be tested for hepatitis in the US. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

## A. Study Design

A multi-center study was conducted to characterize the performance of the Elecsys Anti-HBs II assay on the cobas e 601 analyzer against the reference assay, Elecsys Anti-HBs, with individuals from defined populations. Performance of the Elecsys Anti-HBs II assay was assessed by testing a total of 4047 samples from adult, pediatric and pregnant subjects at increased risk, and vaccination subjects, at three (3) different study sites. All subjects were tested using FDA-approved reference methods. The 4047 subjects were comprised of 2067 adult subjects at increased risk (45.6% female and 54.4% male), 128 pediatric subjects (53.1% female and 46.9% male), 218 pregnant at increased risk subjects, and 70 vaccination subjects (45.7% female and 54.3% male), along with 692 supplemental samples (18.5% female and 81.4% male), 588 pregnant at low risk subjects and 284 specificity samples (57.0% female and 27.5% male), and were tested with the Elecsys Anti-HBs II assay and the Elecsys Anti-HBs assay. The supplemental cohort was used to provide an adequate number for both acute and chronic individuals. The three (3) sites tested the at-risk and supplemental specimens with a full panel of anti-HBc IgM, anti-HBc, HBsAg, HBeAg, anti-HBe, and anti-HBs (reference) for serological characterization. The study included the following races: Caucasian, African-American/Black, Asian, American Indian/Alaskan Native, and Hawaiian Native/Pacific Islander.

## B. Accountability of PMA Cohort

The clinical agreement study involved the testing of 2759 samples Adult at increased risk (2067 prospectively collected and 692 supplemental) for the adult at increased risk (AIR) on six (6) FDA approved reference assays, each detecting a unique serological marker (HBsAg, HBeAg, Anti-HBs, Anti-HBc, Anti-HBc IgM, and Anti-HBe) in order to determine the HBV classification for each of the samples tested.

The following table shows the different HBV specimen classifications.

| Serological classification by FDA-approved HBV panel | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | HBsAg | HBeAg | Anti-HBc IgM | Anti-HBc | Anti-HBe | Anti-HBs |
| Acute | (+) | (+) | (+) | (+) | (-), (+) | (-) |
| Acute | (+) | (+) | (-), (+) | (-) | (-) | (-) |

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| Serological classification by FDA-approved HBV panel | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | HBsAg | HBeAg | Anti-HBc IgM | Anti-HBc | Anti-HBe | Anti-HBs |
| Acute | (+) | (-) | (-) | (-) | (-) | (-) |
| Acute | (+) | (+) | eq | (+) | (-), (+) | (-) |
| Acute | (+) | (-) | (+) | (+) | (-) | (-) |
| Acute | (+) | (-) | eq | (+) | (+) | (-) |
| Acute (late) | (+) | (-) | (+) | (+) | (+) | (-), (+) |
| | | | | | | |
| Chronic | (+) | (+) | (+) | (+) | (+) | (+) |
| Chronic | (+) | (-) | (-) | (+) | (+) | (-), (+) |
| Chronic | (+) | (-) | (-) | (+) | eq | (-) |
| Chronic | (+) | (-) | (-) | (+) | (-) | (-), (+) |
| Chronic | (+) | (+) | (+) | (+) | (-) | (+) |
| Chronic | (+) | (+) | (-) | (+) | (-) | (-), (+) |
| Chronic | (+) | (+) | (-) | (+) | (+) | (-) |
| | | | | | | |
| Early recovery | (-) | (-) | (-) | (+) | (-), eq, (+) | (-) |
| Early recovery | (-) | (-) | (+) | (+) | (-) | (-), (+) |
| Early recovery | (-) | (-) | (+) | (+) | (+) | (-), (+) |
| | | | | | | |
| Recovery | (-) | (-) | (-) | (-), (+) | (+) | (+) |
| Recovery | (-) | (-) | (-) | (+) | (+) | eq |
| Recovery | (-) | (-) | (-) | (+) | eq | (+) |
| | | | | | | |
| Recovered or immune due to natural infection | (-) | (-) | (-) | (+) | (-) | (+), eq |
| | | | | | | |
| HBV vaccine response | (-) | (-) | (-) | (-) | (-) | (+) |
| HBV vaccine response (?) | (-) | (-) | (-) | (-) | (-) | eq |
| | | | | | | |
| Not previously infected | (-) | (-) | (-) | (-) | (-) | (-) |

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| Serological classification by FDA-approved HBV panel | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | HBsAg | HBeAg | Anti-HBc IgM | Anti-HBc | Anti-HBe | Anti-HBs |
| | | | | | | |
| Not interpretable | (-) | (+) | (-) | (+) | (-) | (+) |
| Not interpretable | (-) | (-) | (-) | (-) | (+) | (-) |
| Not interpretable | (-) | (+) | (-) | (+) | (+) | (-) |
| Not interpretable | (-) | (+) | (-) | (-) | (-) | (-), eq, (+) |

The following table shows the total numbers of the HBV Serological Classification for adult at increased risk prospective and retrospective cohorts.

Table 24: Adult AIR Prospective and Retrospective Cohorts by HBV Serological Classification

| HBV Classification | Adult AIR Prospective | Adult AIR Retrospective | Total |
| --- | --- | --- | --- |
| Acute | 7 | 75 | 82 |
| Chronic | 32 | 318 | 350 |
| Early Recovery | 198 | 16 | 214 |
| Recovery | 131 | 199 | 330 |
| Recovered | 248 | 83 | 331 |
| Vaccination | 497 | 0 | 497 |
| Not previously infected | 944 | 1 | 945 |
| Not Interpretable | 10 | 0 | 10 |
| Total | 2067 | 692 | 2759 |

The clinical study also included the following number of evaluable patients for each cohort: 71 evaluable patients for pre- and post- vaccination, 128 evaluable patients for pediatrics, and 806 evaluable patients (119 at increased risk, 16 ex-US, and 243 low risk).

## C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for an anti-HBs II detection study performed in the US. The following tables show the demographics for the different study cohorts.

Table 25: Demographics by Sex for Each Study Cohort

| Sex | Adult AIR | | Pediatric AIR | | Pregnant AIR | | Vaccination | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | n | % | n | % |
| Female | 943 | 45.62 | 68 | 53.13 | 218 | 100.00 | 32 | 45.71 |
| Male | 1124 | 54.38 | 60 | 46.88 | na | na | 38 | 54.29 |
| Total | 2067 | 100.00 | 128 | 100.00 | 218 | 100.00 | 70 | 100.00 |

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| Sex | Supplemental | | Pregnant at Low Risk | | Specificity | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | n | % | n | % |
| Female | 128 | 18.50 | 588 | 100.00 | 162 | 57.04 | 2139 | 52.85 |
| Male | 563 | 81.36 | Na* | na | 78 | 27.46 | 1863 | 46.03 |
| Unknown | 1 | 0.14 | na | na | 44 | 15.49 | 45 | 1.11 |
| Total | 692 | 100.00 | 588 | 100.00 | 284 | 100.00 | 4047 | 100.00 |

*na-not applicable

Table 26: Demographics by Ethnicity for Each Study Cohort

| Ethnicity | Adult AIR | | Pediatric AIR | | Pregnant AIR | | Vaccination | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | n | % | n | % |
| Hispanic / Latino | 536 | 25.93 | 70 | 54.69 | 171 | 78.44 | 5 | 7.14 |
| Not Hisp. / Latino | 1524 | 73.73 | 57 | 44.53 | 31 | 9.63 | 65 | 92.86 |
| unknown | 7 | 0.34 | 1 | 0.78 | 16 | 7.34 | 0 | 0.00 |
| Total | 2067 | 100.00 | 128 | 100.00 | 218 | 100.00 | 70 | 100.00 |
| Ethnicity | Supplemental | | Pregnant At Low Risk | | Specificity | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | n | % | n | % |
| Hispanic / Latino | 7 | 1.01 | 0 | 0.00 | 9 | 3.17 | 798 | 19.72 |
| Not Hisp. / Latino | 30 | 4.34 | 0 | 0.00 | 0 | 0.00 | 1707 | 42.18 |
| unknown | 655 | 94.65 | 588 | 100.00 | 275 | 96.83 | 1542 | 38.10 |
| Total | 692 | 100.00 | 588 | 100.00 | 284 | 100.00 | 4047 | 100.00 |

Table 27: Demograhpics by Race for Each Study Cohort

| Race | Adult AIR | | Pediatric AIR | | Pregnant AIR | | Vaccination | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | n | % | n | % |
| AIANa | 22 | 1.06 | 0 | 0.00 | 1 | 0.46 | 0 | 0.00 |
| Asian | 15 | 0.73 | 4 | 3.13 | 3 | 1.38 | 0 | 0.00 |
| African Am./Black | 1025 | 49.59 | 32 | 25.00 | 31 | 14.22 | 6 | 8.57 |
| Caucasian/White | 949 | 45.91 | 86 | 67.19 | 176 | 80.73 | 63 | 90.00 |
| NHOPIb | 4 | 0.19 | 1 | 0.78 | 1 | 0.46 | 0 | 0.00 |
| Other | 44 | 2.13 | 4 | 3.12 | 4 | 1.83 | 1 | 1.43 |
| Unknown | 8 | 0.39 | 1 | 0.78 | 2 | 0.92 | 0 | 0.00 |
| Total | 2067 | 100.00 | 128 | 100.00 | 218 | 100.00 | 70 | 100.00 |
| Race | Supplemental | | Pregnant At Low Risk | | Specificity | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | n | % | n | % |
| AIAN | 3 | 0.43 | 2 | 0.34 | 0 | 0.00 | 28 | 0.69 |
| Asian | 88 | 12.72 | 10 | 1.70 | 4 | 1.41 | 124 | 3.06 |
| African Am./Black | 1025 | 49.59 | 32 | 25.00 | 31 | 14.22 | 6 | 8.57 |
| Caucasian/White | 949 | 45.91 | 86 | 67.19 | 176 | 80.73 | 63 | 90.00 |
| NHOPIb | 4 | 0.19 | 1 | 0.78 | 1 | 0.46 | 0 | 0.00 |
| Other | 44 | 2.13 | 4 | 3.12 | 4 | 1.83 | 1 | 1.43 |
| Unknown | 8 | 0.39 | 1 | 0.78 | 2 | 0.92 | 0 | 0.00 |
| Total | 2067 | 100.00 | 128 | 100.00 | 218 | 100.00 | 70 | 100.00 |

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Table 28: Demograhpics by Age for Each Study Cohort

| Age | Adult AIR | | Pediatric AIR | | Pregnant AIR | | Vaccination | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | n | % | n | % |
| 2 to 21 | 0 | 0.00 | 128 | 100.00 | 65 | 29.82 | 0 | 0.00 |
| 22 to 29 | 258 | 12.48 | 0 | 0.00 | 95 | 43.58 | 1 | 1.43 |
| 30 to 39 | 369 | 17.85 | 0 | 0.00 | 48 | 22.02 | 4 | 5.71 |
| 40 to 49 | 591 | 28.59 | 0 | 0.00 | 10 | 4.59 | 9 | 12.86 |
| 50 to 59 | 641 | 31.01 | 0 | 0.00 | 0 | 0.00 | 20 | 28.57 |
| 60 to 69 | 187 | 9.05 | 0 | 0.00 | 0 | 0.00 | 26 | 37.14 |
| 70 to 79 | 18 | 0.87 | 0 | 0.00 | 0 | 0.00 | 8 | 11.43 |
| ≥ 80 | 3 | 0.15 | 0 | 0.00 | 0 | 0.00 | 2 | 2.86 |
| Total | 2067 | 100.0 | 128 | 100.0 | 218 | 100.0 | 70 | 100.0 |
| Age range | 22 to 84 years | | 2 to 21 years | | 17 to 44 years | | 22 to 81 years | |
| Median range | 46 years | | 19 years | | 25 years | | 61 years | |
| Age | Supplemental | | Pregnant At Low Risk | | Specificity | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | n | % | n | % |
| 2 to 21 | 4 | 0.58 | 174 | 29.59 | 29 | 10.21 | 400 | 9.88 |
| 22 to 29 | 130 | 18.79 | 288 | 48.98 | 37 | 13.03 | 809 | 19.99 |
| 30 to 39 | 154 | 22.25 | 119 | 20.24 | 36 | 12.68 | 730 | 18.04 |
| 40 to 49 | 209 | 30.20 | 7 | 1.19 | 46 | 16.20 | 872 | 21.55 |
| 50 to 59 | 163 | 23.55 | 0 | 0.00 | 31 | 10.92 | 855 | 21.13 |
| 60 to 69 | 26 | 3.76 | 0 | 0.00 | 27 | 9.51 | 266 | 6.57 |
| 70 to 79 | 6 | 0.87 | 0 | 0.00 | 15 | 5.28 | 47 | 1.16 |
| ≥ 80 | 0 | 0.00 | 0 | 0.00 | 9 | 3.17 | 14 | 0.35 |
| unknown | 0 | 0.00 | 0 | 0.00 | 54 | 19.01 | 54 | 1.33 |
| Total | 692 | 100.00 | 588 | 100.00 | 284 | 100.00 | 4047 | 100.00 |
| Age range | 21 to 78 years | | 15 to 41 years | | 5 to 89 years | | 2 to 89 years | |
| Median age | 43 years | | 24.5 years | | 43 years | | 41 years | |

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D. Safety and Effectiveness Results

1. Safety Results

With regard to safety, as an in vitro diagnostic test, the Elecsys Anti-HBs II involves taking a sample of plasma and serum from a patient. The test therefore presents no more safety hazard to an individual being tested than other tests where blood samples are drawn.

There was one death reported in the vaccination cohort which was determined to be unrelated to the vaccination in the PMA clinical study.

2. Effectiveness Results

The 4047 subjects were comprised of 2067 adult subjects at increased risk (45.6 % female and 54.4 % male), 128 pediatric subjects (53.1 % female and 46.9 % male), 218 pregnant at increased risk subjects, and 70 vaccination subjects (45.7 % female and 54.3 % male), along with 692 supplemental samples (18.5 % female and 81.4 % male), 588 pregnant at low risk subjects and 284 specificity samples (57.0 % female and 27.5 % male), and were tested with the Elecsys Anti-HBs II assay and the Elecsys Anti-HBs assay. The supplemental cohort was used to provide an adequate number for both acute and chronic individuals. The three (3) sites tested the at-risk and supplemental specimens with a full panel of anti-HBc IgM, anti-HBc, HBsAg, HBeAg, anti-HBe, and anti-HBs (reference) for serological characterization. The study included the following races: Caucasian, African-American/Black, Asian, American Indian/Alaskan Native, and Hawaiian Native/Pacific Islander. Key effectiveness outcomes are presented in the tables below.

Specimens were tested using the Elecsys Anti-HBs II on the cobas e 601 immunoassay analyzer and a FDA-approved reference assay to establish the clinical performance characteristics. The following tables compare the Elecsys Anti-HBs II results with the results obtained on an FDA-approved anti-HBs reference assay by HBV disease classification for the different cohorts tested.

Adult At Increased Risk (AIR)

A total of 2067 adults at increased risk were tested on the Elecsys Anti-HBs II and FDA approved reference assay, and the positive and negative percent agreement calculated as shown in the tables below.

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Table 29: Results For Adult AIR Cohort by HBV Classification

| | Elecsys Anti-HBs | | | | | | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| HBV Classification | positive | | indeterminate | | negative | | |
| | Elecsys Anti-HBs II | | | | | | |
| | RXa | NRb | RX | NR | RX | NR | |
| Acute | 0 | 0 | 0 | 0 | 0 | 7 | 7 |
| Chronic | 1 | 0 | 0 | 0 | 0 | 31 | 32 |
| Early Recovery | 5 | 0 | 0 | 0 | 26 | 167 | 198 |
| Recovery | 130 | 0 | 1 | 0 | 0 | 0 | 131 |
| Recovered | 239 | 3 | 4 | 2 | 0 | 0 | 248 |
| HBV Vaccination | 49 | 5 | 1 | 0 | 0 | 0 | 497 |
| Not Previously Infected | 0 | 0 | 0 | 0 | 10 | 934 | 944 |
| Not Interpretable | 2 | 1 | 0 | 1 | 0 | 6 | 10 |
| Total | 868 | 9 | 6 | 3 | 36 | 1145 | 2067 |

$^{\mathrm{a}}$ RX- reactive
$^{\mathrm{b}}$ NR-non-reactive

Table 30: Results for Prospective Adult AIR Cohort by HBV Classification

| | Elecsys Anti-HBs | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | positive | | indeterminate | | negative | | |
| | Elecsys Anti-HBs II | | Elecsys Anti-HBs II | | Elecsys Anti-HBs II | | |
| HBV classification | RX | NR | RX | NR | RX | NR | Total |
| Acute | 0 | 0 | 0 | 0 | 0 | 7 | 7 |
| Chronic | 1 | 0 | 0 | 0 | 0 | 31 | 32 |
| Early recovery | 5 | 0 | 0 | 0 | 26 | 167 | 198 |
| Recovery | 130 | 0 | 1 | 0 | 0 | 0 | 131 |
| Recovered | 239 | 3 | 4 | 2 | 0 | 0 | 248 |
| HBV vaccination | 491 | 5 | 1 | 0 | 0 | 0 | 497 |
| Not previously infected | 0 | 0 | 0 | 0 | 10 | 934 | 944 |
| Not interpretable | 2 | 1 | 0 | 1 | 0 | 6 | 10 |
| Total | 1868 | 9 | 6 | 3 | 36 | 1145 | 2067 |

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Table 31: Performance for Prospective Adult AIR Cohort by HBV Classification

| HBV classification | | | | |
| --- | --- | --- | --- | --- |
| | positive percent agreement | | negative percent agreement | |
| | % (ratio) | 95 % Exact CI | % (ratio) | 95 % Exact CI |
| Acute | n/a (0/0) | n/a (0/0) | 100 (7/7) | 59.0 to 100 |
| Chronic | 100 (1/1) | 2.50 to 100 | 100 (31/31) | 88.8 to 100 |
| Early recovery | 100 (5/5) | 47.8 to 100 | 86.5 (167/193) | 80.9 to 91.0 |
| Recovery | 100 (130/130) | 97.2 to 100 | 0.00 (0/1) | 0.00 to 97.5 |
| Recovered | 98.0 (239/244) | 95.3 to 99.3 | 0.00 (0/4) | 0.00 to 60.2 |
| HBV vaccination | 99.0 (491/496) | 97.7 to 99.7 | 0.00 (0/1) | 0.00 to 97.5 |
| Not previously infected | n/a (0/0) | n/a (0/0) | 98.9 934/944) | 98.1 to 99.5 |
| Not interpretable | 50.0 (2/4) | 6.76 to 93.2 | 100 (6/6) | 54.1 to 100 |
| Total | 98.6 (868/880) | 97.6 to 99.3 | 96.5 (1145/1187) | 5.3 to 97.4 |

Additional Samples were sourced from vendors (retrospective) to enrich the different HBV classifications. The following tables show the results and performance.

Table 32: Results for Retrospective Adult AIR Cohort by HBV Classification

| HBV Classification | Elecsys Anti-HBs Immunoassay | | | | | | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | positive | | indeterminate | | negative | | |
| | Elecsys Anti-HBs II | | | | | | |
| | RX | NR | RX | NR | RX | NR | |
| Acute | 3 | 0 | 0 | 0 | 2 | 70 | 75 |
| Chronic | 7 | 4 | 0 | 0 | 2 | 305 | 318 |
| Early Recovery | 0 | 0 | 0 | 0 | 5 | 11 | 16 |
| Recovery | 197 | 0 | 1 | 1 | 0 | 0 | 199 |
| Recovered | 80 | 0 | 3 | 0 | 0 | 0 | 83 |
| Not Previously Infected | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Total | 287 | 4 | 4 | 1 | 9 | 387 | 692 |

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Table 33: Performance for Retrospective Adult AIR Supplemental Cohort by HBV Classification

| HBV Classification | Positive Percent Agreement, PPA (%) | 95% Exact Confidence Interval | Negative Percent Agreement, NPA (%) | 95% Exact Confidence Interval |
| --- | --- | --- | --- | --- |
| Acute | 100.00 (3/3) | 29.24 to 100.00 | 97.22 (70/72) | 90.32 to 99.66 |
| Chronic | 63.64 (7/11) | 30.79 to 89.07 | 99.35 (305/307) | 97.67 to 99.92 |
| Early Recovery | na (0/0) | na | 68.75 (11/16) | 41.34 to 88.98 |
| Recovery | 99.49 (197/198) | 97.22 to 99.99 | 0.00 (0/1) | 0.00 to 97.50 |
| Recovered | 100.00 (80/80) | 95.49 to 100.00 | 0.00 (0/3) | 0.00 to 70.76 |
| Not Previously Infected | na (0/0) | na | 100.00 (1/1) | 2.50 to 100.00 |
| Total | 98.29 (287/292) | 96.05 to 99.44 | 96.75 (387/400) | 94.51 to 98.26 |

Table 34: Combined Results for Prospective and Retrospective Adult AIR Subjects

| | Elecsys Anti-HBs | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | positive | | indetermine | | negative | | |
| | Elecsys Anti-HBs II | | Elecsys Anti-HBs II | | Elecsys Anti-HBs II | | |
| HBV classification | RX | NR | RX | NR | RX | NR | Total |
| Acute | 3 | 0 | 0 | 0 | 2 | 77 | 82 |
| Chronic | 8 | 4 | 0 | 0 | 2 | 336 | 350 |
| Early recovery | 5 | 0 | 0 | 0 | 31 | 178 | 214 |
| Not interpretable | 2 | 1 | 1 | 1 | 0 | 6 | 10 |
| Not previously infected | 0 | 0 | 0 | 0 | 10 | 935 | 945 |
| Recovered | 319 | 3 | 2 | 2 | 0 | 0 | 331 |
| Recovery | 327 | 0 | 1 | 1 | 0 | 0 | 330 |
| Vaccination | 491 | 5 | 0 | 0 | 0 | 0 | 497 |
| Total | 1155 | 13 | 4 | 4 | 45 | 1532 | 2759 |

Table 35: Combined Performance for Prospective and Retrospective Adult AIR Subjects

| HBV classification | | | | |
| --- | --- | --- | --- | --- |
| | Positive percent agreement | | Negative percent agreement | |
| | % (ratio) | 95 % Exact CI | % (ratio) | 95 % Exact CI |
| Acute | 100 (3/3) | 29.2 to 100 | 97.5 (77/79) | 91.2 99.7 |
| Chronic | 66.7 (8/12) | 34.9 to 90.1 | 99.4 (336/338) | 97.9 to 99.9 |

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| HBV classification | | | | |
| --- | --- | --- | --- | --- |
| | Positive percent agreement | | Negative percent agreement | |
| | % (ratio) | 95 % Exact CI | % (ratio) | 95 % Exact CI |
| Early recovery | 100 (5/5) | 47.8 to 100 | 85.2 (178/209) | 79.6 to 89.7 |
| Recovery | 99.7 (327/328) | 98.3 to 100 | 0.00 (0/2) | 0.00 to 84.2 |
| Recovered | 98.5 (319/324) | 96.4 to 99.5 | 0.00 (0/7) | 0.00 to 41.0 |
| Not previously infected | 98.5 (319/324) | n/a | 98.9 (935/945) | 98.1 to 99.5 |
| Vaccination | n/a (0/0) | 97.7 to 99.7 | 0.00 (0/1) | 0.00 to 97.5 |
| Not interpretable | 50.0 (2/4) | 6.76 to 93.2 | 100 (6/6) | 54.1 to 100 |
| Total | 98.6 (1155/1172) | 97.7 to 99.2 | 96.5 (1532/1587) | 5.5 to 97.4 |

Vaccination

Pre- and post-vaccination samples were collected from a minimum of 71 subjects who were inoculated with one of three (3) US-approved hepatitis B vaccines. Testing of the pre-vaccination samples found all 71 samples to be negative for anti-HBs, but one subject was anti-HBc positive and was therefore excluded. All 17 nonresponder specimens were negative/non-reactive in another FDA-approved anti-HBs assay. The following table shows the results.

Table 36: Performance for Vaccination Cohort

| | Elecsys Anti-HBs | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Pre-vaccination | | | Post-vaccination | | | Total | | |
| Elecsys Anti-HBs II | Pos | Ind | Neg | Pos | Ind | Neg | Pos | Ind | Neg |
| Reactive | 0 | 0 | 0 | 52 | 0 | 0 | 52 | 0 | 0 |
| Non-reactive | 0 | 0 | 70 | 1 | 0 | 17 | 1 | 0 | 87 |
| Total | 0 | 0 | 70 | 53 | 0 | 17 | 53 | 0 | 87 |
| PPAa | (0/0) | | | 98.1 (52/53) | | | 98.1 (52/53) | | |
| 95 % CIb | n/a | | | 89.9 to 100.0 | | | 89.9 to 100.0 | | |
| NPAc | 100 (70/70) | | | 100 (17/17) | | | 100 (87/87) | | |
| 95 % CI | 94.9 to 100 | | | 80.5 to 100 | | | 95.9 to 100 | | |

aPPA-positive percent agreement
bCI-confidence interval
cNPA-negative percent agreement

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# Pediatric

The pediatric increased-risk for hepatitis subgroup was acquired from the US-prospective sample collection to demonstrate the clinical performance of the Elecsys Anti-HBs II assay in subjects from 2 years through and including 21 years of age. A total of 128 samples were collected. The following table shows the results.

Table 37: Performance for Pediatric Cohort

| | Elecsys Anti-HBs Immunoassay | | | |
| --- | --- | --- | --- | --- |
| Elecsys Anti-HBs II | positive | indeterminate | negative | Total |
| Positive (pos) | 55 | 1 | 1 | 57 |
| Negative (neg) | 3 | 0 | 68 | 71 |
| Total | 58 | 1 | 69 | 128 |
| PPA | 94.8 (55/58) | | | |
| 95% CI | 85.6 to 98.9 | | | |
| NPA | 97.1 (68/70) | | | |
| 95% CI | 90.0 to 99.7 | | | |

In addition, there were 59 specimens from pregnant young women that met the age criteria for pediatric subjects at increased risk for hepatitis obtained in the prospective collection. Thirty-four (34) of these specimens were concordantly negative between the Elecsys Anti-HBs II assay and the Elecsys Anti-HBs assay, while 23 were concordantly positive. There was 1 positive and 1 negative in the test assay that was indeterminate with the reference assay. The NPA for this pregnant pediatric sub-group was $97.1\%$ (34/35) with confidence limits of 85.1 to $99.9\%$ . The PPA was $95.8\%$ (23/24) with confidence limits of 78.9 to $99.9\%$ .

# Pregnant

Pregnant subjects with increased risk for hepatitis (n=218) and with low risk for hepatitis (remnant samples n=588) were tested and analyzed. The results are shown in the following table.

Table 38: Performance for Pregnant Cohort

| | Elecsys Anti-HBs | | |
| --- | --- | --- | --- |
| Elecsys Anti-HBs II | positive | indeterminate | negative |
| Reactive | 420 | 4 | 8 |
| Non-reactive | 3 | 3 | 368 |
| Total | 423 | 7 | 376 |
| PPA | 98.6 (420/426) | | |
| 95 % CI | 97.0 to 99.5 | | |

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| | Elecsys Anti-HBs | | |
| --- | --- | --- | --- |
| Elecsys Anti-HBs II | positive | indeterminate | negative |
| NPA | 96.8 (368/380) | | |
| 95 % CI | 94.6 to 98.4 | | |

3. **Subgroup Analyses**
The study design enabled an assessment of assay performance by subgroup as depicted in the tables above which show subjects stratified by cohort.

4. **Pediatric Extrapolation**
In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

E. **Financial Disclosure**
The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 11 investigators. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data.

XI. **PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION**
In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Microbiology Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

XII. **CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES**

A. **Effectiveness Conclusions**
The effectiveness of the Elecsys Anti-HBs II for the quantitative detection of antibodies to hepatitis B surface antigen in human serum and plasma (potassium EDTA) samples is supported by the clinical study results. The results of this test may be used as an aid in the diagnosis of HBV infection in patients with symptoms of hepatitis and as an aid in determination of susceptibility to HBV infection for individuals prior to or following HBV vaccination. See Section X.D.2 for Effectiveness Results.

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B. Safety Conclusions

The risks of the device are based on nonclinical laboratory studies as well as data collected in a clinical study conducted to support PMA approval as described above. Based on the results of these studies, the Elecsys Anti-HBs II when used according to the manufacturer’s instructions can aid the physician in the diagnosis of HBV infection and as an aid in determination of susceptibility to HBV infection for individuals prior to or following HBV vaccination.

C. Benefit-Risk Determination

The probable benefits of the device are also based on data collected in the clinical study conducted to support PMA approval as described above. The benefits of the assay are as part of a hepatitis B panel, the appropriate determination of HBV seroconversion as part of disease management and treatment. Treatment for appropriate patients can mitigate the sequelae of hepatitis B infection and may result in improved morbidity and mortality in these patients. Known sequelae of hepatitis B infection include continued symptoms, increases in all-cause mortality, liver disease-related complications and death, hepato-cellular carcinoma rates, and need for liver transplantation. Additionally, management and appropriate treatment for hepatitis B infection can potentially decrease transmission and disease burden in the general population and particularly in populations at high risk for hepatitis B infection. While the performance of the device in the clinical study suggests that patients will benefit from the assay, low prevalence of certain HBV classifications is a source of potential uncertainty when analyzing the samples. The wide confidence intervals for those subgroups is expected due to the biology of hepatitis B infection and is acceptable.

The risks associated with the device, when used as intended, are those related to the risk of false test results, failure to correctly interpret the test results and failure to correctly operate the instrument.

The risks associated with the device, when used as intended, are those related to the risk of false test results, failure to correctly interpret the test results, and failure to correctly operate the device.

Risks of false positive results when the device is used as an aid in the diagnosis of hepatitis B virus (HBV) infection in patients with symptoms of hepatitis or who may be at risk for HBV infection include improper patient management, including treatment for hepatitis B with antiviral medication. Antiviral medication has risks including toxicity and more rarely allergic reactions. Over time, viral resistance in patients who are coinfected but undiagnosed with other viruses that are treated with the same antiviral medication, such as HIV, can lead to viral resistance, however the chance of an undiagnosed co-infection in a patient treated for hepatitis B is unlikely.

Risks of false positive results when the device is used as an aid in the determination of susceptibility to HBV infection in individuals prior to or following HBV

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vaccination or where vaccination status is unknown includes leading a provider to falsely believe that a patient has been vaccinated in the past and/or has current immunity when the patient, in fact, does not. This could lead to a missed opportunity to vaccinate a patient in whom Hepatitis B vaccination is indicated. Vaccination for appropriate patients can mitigate the sequelae of hepatitis B infection and may result in improved morbidity and mortality in these patients. Known sequelae of hepatitis B infection include continued symptoms, increases in all-cause mortality, liver disease-related complications and death, hepatocellular carcinoma rates, and need for liver transplantation. Vaccination for hepatitis B infection can potentially decrease transmission and disease burden in the general population and particularly in populations at high risk for hepatitis B infection.

Risks of false negative results 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 include potentially missing and not treating a patient who has hepatitis B infection. Missing and not treating a patient with hepatitis B infection whose clinical picture warrants antiviral treatment could result in the known sequelae of HBV infection and may result in high morbidity and mortality in these patients. Additionally, missing a diagnosis of hepatitis B infection will not allow for clinicians to potentially decrease transmission and disease burden in the general population, particularly in populations at high risk for hepatitis B infection.

Risks of false negative results 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 include unnecessary repeated vaccination for hepatitis B. Although vaccination has risks such as local reactions, and serious adverse events due to Hepatitis B vaccination are rare, administration of extra doses of single-antigen hepatitis B vaccine is not generally harmful. In fact, it is common practice to administer higher dose vaccinations in an accelerated schedule for patients undergoing organ transplantation, for example.

1. Patient Perspective
This submission either did not include specific information on patient perspectives or the information did not serve as part of the basis of the decision to approve or deny the PMA for this device.

In conclusion, given the available information above, the data support that for the claimed intended use the probable benefits outweigh the probable risks.

D. Overall Conclusions

The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use. The probable clinical benefits outweigh the potential risks for the proposed assay considering the performance of the device in the clinical study and the low risk and associated risk mitigations in clinical practice. The proposed assay labeling will

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facilitate accurate assay implementation and interpretation of results. The clinical performance observed suggests that errors will be uncommon and that the assay may provide substantial benefits to patients as an accurate and sensitive aid in the diagnosis of HBV infection when used in conjunction with other laboratory results and clinical information and as an aid in determination of susceptibility to HBV infection for individuals prior to or following HBV vaccination.

## XIII. CDRH DECISION

CDRH issued an approval order on February 23, 2021.

The applicant’s manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

## XIV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling.

Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.

Post-approval Requirements and Restrictions: See approval order.

PMA P190034: FDA Summary of Safety and Effectiveness Data
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