ARCHITECT HBSAG QUALITATIVE, QUALITATIVE CONFIRMATORY, CONFIRMATORY MANUAL DILUENT, CALIBRATORS, AND CONTROLS

P110029 · Abbott Laboratories · LOM · Apr 12, 2012 · Microbiology

Device Facts

• Record ID: P110029
• Device Name: ARCHITECT HBSAG QUALITATIVE, QUALITATIVE CONFIRMATORY, CONFIRMATORY MANUAL DILUENT, CALIBRATORS, AND CONTROLS
• Applicant: Abbott Laboratories
• Product Code: LOM · Microbiology
• Decision Date: Apr 12, 2012
• Decision: APRL
• Regulation: 21 CFR 866.3172
• Device Class: Class 2
• Attributes: Pediatric

Intended Use

The ARCHITECT HBsAg Qualitative assay is a chemiluminescent microparticle immunoassay (CMIA) for the qualitative detection of hepatitis B surface antigen (HBsAg) in human adult and pediatric serum and plasma and neonate serum. The assay may also be used to screen for HBV infection in pregnant women to identify neonates who are at risk for acquiring hepatitis B during the perinatal period. Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of infection with the hepatitis B virus (HBV) (state of infection or associated disease not determined) in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis B infection. Not intended for use in screening blood, plasma, or tissue donors. The ARCHITECT HBsAg Qualitative Confirmatory assay is a chemiluminescent microparticle immunoassay (CMIA) for the qualitative confirmation of the presence of hepatitis B surface antigen (HBsAg) in human adult and pediatric serum and plasma and neonate serum by means of specific antibody neutralization. Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of infection with the hepatitis B virus (HBV) (state of infection or associated disease not determined) in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis B infection. Not intended for use in screening blood, plasma, or tissue donors.

Device Story

ARCHITECT HBsAg Qualitative and Confirmatory assays are CMIA-based in vitro diagnostic tests performed on the ARCHITECT i System. Input: human serum/plasma/neonate serum. Principle: one-step (Qualitative) or two-step neutralization (Confirmatory) immunoassay using anti-HBs coated paramagnetic microparticles and acridinium-labeled conjugate. Output: chemiluminescent signal (RLUs) measured by system optics; results expressed as S/CO ratio. Used in clinical laboratories by technicians. Results assist physicians in diagnosing HBV infection status. Benefits: early detection of HBV infection, identification of high-risk neonates for prophylactic intervention (HBIG/vaccine).

Clinical Evidence

Prospective multi-center study (n=2800) evaluated precision and agreement against comparator HBsAg assays. Populations included increased risk (n=1279), signs/symptoms of hepatitis (n=675), acute/chronic HBV (n=126), and pregnant females (n=720). Positive percent agreement (PPA) for increased risk/symptoms population was 97.83% (95% CI: 92.37-99.74%); negative percent agreement (NPA) was 99.30% (95% CI: 98.81-99.63%). Pediatric population (n=210) showed 83.33% PPA and 99.51% NPA. Bench testing confirmed analytical sensitivity (LoD ≤ 0.002 IU/mL), genotype detection (A-H), and mutant detection (e.g., Thr-123-Ala, Gly-145-Arg).

Technological Characteristics

CMIA detection technology. Reagents: anti-HBs coated paramagnetic microparticles, acridinium-labeled conjugate, ancillary wash buffer, pre-trigger (1.32% H2O2), trigger (0.35 N NaOH). Form factor: automated immunoassay analyzer (ARCHITECT i System). Connectivity: standalone analyzer. Preservatives: ProClin 300, ProClin 950, sodium azide. Materials: mouse monoclonal/goat IgG antibodies, bovine serum albumin, human plasma stabilizers.

Indications for Use

Indicated for qualitative detection and confirmation of HBsAg in human adult, pediatric, and neonate serum and plasma. Used for individuals with signs/symptoms of hepatitis, persons at risk for HBV infection, and screening pregnant women to identify neonates at risk for perinatal HBV acquisition. Not for blood, plasma, or tissue donor screening.

Regulatory Classification

Identification

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

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) The specimen types for which the device has been cleared, and that use of this assay with specimen types other than those specifically cleared for this device may result in inaccurate assay results. (B) When appropriate, performance characteristics of the assay have not been established in populations of immunocompromised or immunosuppressed patients or other populations where assay performance may be affected. (C) Diagnosis of hepatitis B infection should not be established on the basis of a single assay result but should be determined by a licensed healthcare professional in conjunction with the clinical presentation, history, and other diagnostic procedures. (D) Detection of HBV antigens indicates a current infection with hepatitis B virus but does not differentiate between acute or chronic infection. False reactive HbsAg result may occur for up to 2 weeks after vaccination with HbsAg containing vaccine. (E) Current methods for the detection of hepatitis B antigens may not detect all potentially infected individuals. A non-reactive assay result does not exclude the possibility of exposure to or infection with hepatitis B virus. A non-reactive assay result in individuals with prior exposure to hepatitis B may be due to but not limited to antigen levels below the detection limit of this assay or lack of antigen reactivity to the antibodies in this assay. HBV mutants lacking the ability to produce antigens have been reported. These may occur as “escape” mutants in the presence of anti-HBV antibodies and such patients may be infectious. (F) Results obtained with this assay may not be used interchangeably with results obtained with a different manufacturer's assay. (2) Design verification and validation must include the following: (i) A detailed device description, including all parts that make up the device, ancillary reagents required but not provided, an explanation of the device methodology, design of the capture antibody(ies), external controls, and computational path from collected raw data to reported result ( *e.g.,* how collected raw signals are converted into a reported signal and result), as applicable to the detection method and device design.(ii) For devices with assay calibrators, the design and composition of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a standardized reference material that FDA has determined is appropriate ( *e.g.,* a recognized consensus standard). In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance or approval, or when there is a transition to a new calibration standard.(iii) Documentation and characterization ( *e.g.,* supplier, determination of identity, purity, and stability) of all critical reagents (including description of the capture antibody(ies)), and protocols for maintaining product integrity throughout its labeled shelf life.(iv) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on assay performance. (v) Final release criteria to be used for manufactured assay lots with appropriate evidence that lots released at the extremes of the specifications will meet the identified analytical and clinical performance characteristics as well as stability. (vi) Stability studies for reagents must include documentation of an assessment of real-time stability for multiple reagent lots using the indicated specimen types and must use acceptance criteria that ensure that analytical and clinical performance characteristics are met when stability is assigned based on the extremes of the acceptance range. (vii) All stability protocols, including acceptance criteria. (viii) Final release assay results for each lot used in clinical studies. (ix) Reproducibility study data that includes the testing of three independent production lots. (x) Detailed documentation of analytical performance studies conducted, as appropriate to the technology, specimen types tested, and intended use of the device, including, the limit of blank (LoB), limit of detection (LoD), cutoff, precision (reproducibility) including lot-to-lot and/or instrument-to-instrument precision, interference, cross reactivity, carryover, hook effect, seroconversion panel testing, matrix equivalency, prominent mutants/variants detection ( *e.g.,* for HbsAg), specimen stability, reagent stability, and cross-genotype antigen detection sensitivity, when appropriate.(xi) Analytical sensitivity of the assay that is the same or better than that of other cleared or approved assays. (xii) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review. (xiii) Detailed documentation and results from a clinical study. Performance must be analyzed relative to an FDA cleared or approved HBV antigen assay or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with an appropriate number of HBV reactive and non-reactive samples in applicable risk and disease categories, and any applicable confirmatory testing. Additional relevant patient groups must be validated as appropriate. The samples must include prospective (sequential) samples for each identified specimen type and, as appropriate, additional characterized clinical samples. Samples must be sourced from geographically diverse areas. This study must be conducted in the appropriate settings by the intended users to demonstrate clinical performance.

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA
(SSED)

I. GENERAL INFORMATION

Device Generic Name: Hepatitis B Surface Antigen
Hepatitis B Surface Antigen Confirmatory

Device Trade Name: ARCHITECT HBsAg Qualitative
ARCHITECT HBsAg Qualitative Confirmatory
ARCHITECT HBsAg Qualitative Confirmatory Manual
Diluent
ARCHITECT HBsAg Qualitative Calibrators
ARCHITECT HBsAg Qualitative Controls

Applicant's Name and Address:
Abbott Laboratories
100 Abbott Park Road
Dept. 09V6, Bldg. AP5 - 2
Abbott Park, IL 60064-6095

Date(s) of Panel Recommendation: Not applicable
Premarket Approval Application (PMA) Number: P110029
Date of FDA Notice of Approval: April 12, 2012
Expedited: Not applicable

II. INDICATIONS FOR USE

1. ARCHITECT HBsAg Qualitative.

The ARCHITECT HBsAg Qualitative assay is a chemiluminescent microparticle immunoassay (CMIA) for the qualitative detection of hepatitis B surface antigen (HBsAg) in human adult and pediatric serum and plasma and neonate serum. The assay may also be used to screen for HBV infection in pregnant women to identify neonates who are at risk for acquiring hepatitis B during the perinatal period. Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of infection with the hepatitis B virus (HBV) (state of infection or associated disease not determined)

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in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis B infection. Not intended for use in screening blood, plasma, or tissue donors.

## 2. ARCHITECT HBsAg Qualitative Confirmatory

The ARCHITECT HBsAg Qualitative Confirmatory assay is a chemiluminescent microparticle immunoassay (CMIA) for the qualitative confirmation of the presence of hepatitis B surface antigen (HBsAg) in human adult and pediatric serum and plasma and neonate serum by means of specific antibody neutralization. Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of infection with the hepatitis B virus (HBV) (state of infection or associated disease not determined) in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis B infection. Not intended for use in screening blood, plasma, or tissue donors.

## 3. ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent

The ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent is used for manually diluting specimens for testing on the ARCHITECT i System using the ARCHITECT HBsAg Qualitative Confirmatory reagent kit. The performance of the ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent has not been established with any other HBsAg assays.

## 4. ARCHITECT HBsAg Qualitative Calibrators

The ARCHITECT HBsAg Qualitative Calibrators are for the calibration of the ARCHITECT i System when used for qualitative detection of the presence of hepatitis B surface antigen (HBsAg) using the ARCHITECT HBsAg Qualitative and HBsAg Qualitative Confirmatory reagent kits. The performance of the ARCHITECT HBsAg Qualitative Calibrators has not been established with any other HBsAg assays.

## 5. ARCHITECT HBsAg Qualitative Controls

The ARCHITECT HBsAg Qualitative Controls are used for monitoring the performance of the ARCHITECT i System (reagents, calibrators, and instrument) when used for the qualitative detection of hepatitis B surface antigen (HBsAg) using the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory reagent kits. The performance of the ARCHITECT HBsAg Qualitative Controls has not been established with any other HBsAg assays.

## III. CONTRAINDICATIONS

None.

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the ARCHITECT HBsAg Qualitative, the ARCHITECT HBsAg Qualitative Confirmatory, the ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent, the ARCHITECT HBsAg Qualitative Calibrators and the ARCHITECT HBsAg Qualitative Controls labeling.

# V. DEVICE DESCRIPTION

## Kit Configurations and Components

The ARCHITECT HBsAg Qualitative reagent kit is comprised of the following three components:

- 1 bottle anti-HBs (mouse, monoclonal, IgM, IgG) coated microparticles in MES buffer with protein (bovine serum albumin) stabilizer.
- 1 bottle anti-HBs (mouse, monoclonal, IgG) and anti-HBs (goat IgG) acridinium-labeled conjugate in phosphate buffer with human plasma and protein (bovine serum albumin, fetal bovine serum, goat IgG, mouse IgG) stabilizers.
- 1 bottle ancillary wash buffer containing MES buffer.
- ProClin 300 and ProClin 950 were added as preservatives to each of the three components.

The ARCHITECT HBsAg Qualitative Confirmatory reagent kit is comprised of the following five components:

- 1 bottle anti-HBs (mouse, monoclonal, IgM, IgG) coated microparticles in MES buffer with protein (bovine serum albumin) stabilizer.
- 1 bottle anti-HBs (mouse, monoclonal, IgG) and anti-HBs (goat, IgG) acridinium-labeled conjugate in phosphate buffer with human plasma and protein (bovine serum albumin, fetal bovine serum, goat IgG, mouse IgG) stabilizers.
- 1 bottle ancillary wash buffer containing MES buffer.
- 1 bottle (2.4 mL) Pre-Treatment 1 containing recalcified human plasma reactive for anti-HBs.
- 1 bottle (2.4 mL) Pre-Treatment 2 containing recalcified human plasma.
- ProClin 300 and ProClin 950 were added as preservatives to each of the three components.

The ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent contains:

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- 1 bottle of ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent. The manual diluent contains recalcified human plasma. Preservatives: ProClin 950 and sodium azide.

The ARCHITECT HBsAg Calibrators contain:

- 2 bottles of ARCHITECT HBsAg Qualitative Calibrators. Calibrator 1 contains inactivated purified human HBsAg (subtype ad) in phosphate buffer with human plasma and protein (bovine serum albumin) stabilizers. Preservatives: ProClin 300 and ProClin 950.
- Calibrator 2 contains recalcified human plasma. Preservatives: ProClin 950 and sodium azide.

The ARCHITECT HBsAg Controls contain:

- 2 bottles of ARCHITECT HBsAg Qualitative Controls. The Negative Control contains recalcified human plasma. Preservatives: ProClin 950 and sodium azide.
- The Positive Control contains inactivated purified human HBsAg (subtypes ad/ay) in phosphate buffer with human plasma and protein (bovine serum albumin) stabilizers. The positive control is blue and contains Acid Blue No. 9. Preservatives: ProClin 300 and ProClin 950.

In addition, the following components are required for the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory reagent kits:

- ARCHITECT i System is an analyzer designed to perform fully-automated immunoassay tests based on the use of CMIA detection technology.
- ARCHITECT i Pre-Trigger Solution contains 1.32% (w/v) hydrogen peroxide.
- ARCHITECT i Trigger Solution contains 0.35 N sodium hydroxide.
- ARCHITECT i Wash Buffer contains phosphate buffered saline solution. Preservatives: antimicrobial agents.

## Assay Principle and Format

### ARCHITECT HBsAg Qualitative

The assay is a one-step assay, ancillary wash buffer is added in a second incubation step, so the assay performs a two-step assay protocol. Sample, anti-HBs coated paramagnetic microparticles, and anti-HBs acridinium-labeled conjugate are combined to create a reaction mixture. HBsAg in the sample binds to the anti-HBs coated microparticles and the anti-HBs acridinium labeled conjugate. After washing, ancillary wash buffer is added to the reaction mixture. Following another wash cycle, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative

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light units (RLUs). A direct relationship exists between the amount of HBsAg in the sample and the RLUs detected by the ARCHITECT system optics.

The presence or absence of HBsAg in the sample is determined by comparing the chemiluminescent signal in the reaction to the cutoff signal determined from an active calibration. If the chemiluminescent signal in the specimen is greater than or equal to the cutoff signal, the sample is considered reactive for HBsAg.

## ARCHITECT HBsAg Qualitative Confirmatory

The assay consists of two single tests that are both one-step pre-treatment immunoassays. Ancillary wash buffer is added in a second incubation step, so the assay performs a two-step assay protocol. Sample and Pre-Treatment 1 reagent are combined in a reaction vessel (RV) and incubated. When HBsAg is present in the sample, it is neutralized by the anti-HBs in Pre Treatment 1. An aliquot of the pretreated sample, anti-HBs coated paramagnetic microparticles, and anti-HBs acridinium-labeled conjugate are combined to create a reaction mixture. Any non-neutralized HBsAg present in the sample binds to the anti-HBs coated microparticles and the anti-HBs acridinium labeled conjugate. The neutralized HBsAg is blocked from forming a sandwich with acridinium labeled anti-HBs conjugate and anti-HBs microparticles. After washing, ancillary wash buffer is added to the RV and incubated. Following another wash cycle, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as RLUs. A direct relationship exists between the amount of HBsAg in the sample and the RLUs detected by the ARCHITECT system optics.

This sequence is repeated for the sample and Pre-Treatment 2 reagent, except Pre Treatment 2 does not contain anti-HBs and will not neutralize HBsAg in the sample. If the signal for the non-neutralized sample (incubated with Pre Treatment 2) result is greater than or equal to the cutoff of $0.70\mathrm{S / CO}$ and the signal of the neutralized sample (incubated with Pre Treatment 1) is reduced by at least $50\%$ compared to the non-neutralized sample, the sample is considered confirmed positive for HBsAg.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

The patient's medical history and thorough physical examination, in addition to hepatitis serology, determination of liver enzyme levels, and biopsy of the liver, will provide further information on the status of a hepatitis B viral infection.

Alternative procedures for the detection of HBV in human adult and pediatric serum and plasma and neonatal serum depend on the detection of HBV deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) assays or nucleic acid testing (NAT), or the detection of HBV antigens and antibodies by

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commercially available assays that are licensed or approved in the United States (US).

## VII. MARKETING HISTORY

The ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory reagent kits, ARCHITECT HBsAg Qualitative Calibrators and Controls have not been marketed in the United States or any foreign country.

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

When used according to the instructions in the package insert, there are no known direct adverse effects of this device on the health of the user. Failure of the test to perform as indicated or human error during performance of the test may lead to a false diagnosis and improper patient management. Below is a list of the potential adverse effects associated with the use of the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory reagent kits, ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent, ARCHITECT HBsAg Qualitative Calibrators and Controls:

- Failure of the device to perform as indicated or human error in use of the device may lead to a false result.
- A false positive result using an HBsAg assay is not considered a patient or public health concern as a positive result in a clinical lab setting is usually followed up with supplemental testing. Either additional HBV marker testing is performed or an HBsAg positive result is confirmed by neutralization. An exception to this is using HBsAg tests to screen pregnant women for the presence of HBsAg. This testing helps to determine if a neonate is at high risk of acquiring HBV during the prenatal period.
- Pregnant women are tested during an early prenatal visit. If they are HBsAg nonreactive during this testing, and at high risk for HBV infection, they are re-tested during the third trimester. If the result is positive, it is recommended that hepatitis 3 immune globulin (HBIG) and vaccine be provided to the newborn within 12 hours of birth. If an assay is false positive and the newborn receives HBIG, the newborn would be exposed to the risks of receiving a human source product.
- The risks of a false negative result in a diagnostic setting are highest when testing pregnant women because HBsAg may be the only marker used. If the result is negative then the child is vaccinated within 2 months of birth. If the result is incorrect (false negative), then the neonate is at a higher risk of acute and chronic HBV infection, since HBIG and vaccine would not be provided within 12 hours of birth.

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- From time to time false negative results due to gene mutation have been reported for the HBsAg assays produced by a number of different manufacturers. Because of the complexity of the mutations that can occur, no manufacturer can guarantee to detect all patients.
- A false positive result using an HBsAg confirmatory neutralization procedure is not considered a patient or public health concern because in order for a false positive to occur, the control sample (non-neutralized result) and the percent neutralization (in the neutralized tube) would both have to be incorrect for a reported false positive result. If this situation were to occur, the implications would be the same as described for false positive results for HBsAg assays.
- A false negative result using an HBsAg confirmatory neutralization procedure could occur if the neutralized sample were incorrect either due to a falsely increased signal with the neutralized sample, or due to some other malfunction, laboratory or technician error when assayed. A falsely increased signal could be interpreted as a failure to neutralize. If this situation were to occur, the implications would be the same as described for false negative results for HBsAg.

## IX. SUMMARY OF NONCLINICAL LABORATORY STUDIES

Nonclinical studies were performed at Abbott Laboratories to evaluate the performance characteristics of the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays. The studies are described below.

### Assay Cutoff Determination

The presence or absence of HBsAg in the sample is determined by comparing the chemiluminescent signal in the reaction to the cutoff RLU determined from an active ARCHITECT HBsAg Qualitative or ARCHITECT HBsAg Qualitative Confirmatory calibration. If the sample RLU is greater than or equal to the cutoff RLU, the sample is considered reactive for HBsAg. The ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assay results are expressed as a ratio (S/CO) of the sample RLU to the cutoff RLU. The S/CO is calculated using the equation:

$$
\mathrm{S/CO} = \frac{\text{Sample RLU}}{\text{Cutoff RLU}}
$$

To select the appropriate cutoff RLU for ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory, negative and known positive specimens were tested to optimize the sensitivity and specificity performance by varying the cutoff negative and positive multiplier factors.

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The following cutoff RLU equation and assay cutoff were selected for ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays:

$$
\text{Cutoff RLU} = (\text{Cal 1 Mean RLU} \times 0.0575) + (\text{Cal 2 Mean RLU} \times 0.8)
$$

The value 1.00 S/CO was selected to be the ARCHITECT HBsAg Qualitative assay cutoff.

The value 0.70 S/CO was selected to be the ARCHITECT HBsAg Qualitative Confirmatory assay cutoff. This cutoff value was chosen to ensure the assay will detect a low-level reactive specimen from the ARCHITECT HBsAg Qualitative assay and compensates for the dilution effect of the assay pretreatment reagents on the specimen.

The confirmation of the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory cutoffs of 1.00 S/CO and 0.70 S/CO, respectively, was demonstrated through nonclinical laboratory studies (within-laboratory precision, seroconversion sensitivity, and analytical sensitivity) and the clinical investigation (system reproducibility and method comparison).

## Within-Laboratory Precision (20-Day)

A 20-day precision study was conducted to evaluate the precision performance of the ARCHITECT HBsAg Qualitative assay based on guidance from the NCCLS document EP5-A2. Testing was performed on 3 ARCHITECT instruments (2 i 2000 SR and 1 i 2000) using 3 lots of reagents, 3 lots of calibrators, and 1 lot of controls. Each reagent lot was matched with a different lot of calibrator. A single calibration per reagent lot was performed on each instrument by testing the calibrators in replicates of 3. The calibration generated for each reagent lot was stored on each instrument for the duration of the study. The controls and panels were tested with a minimum of 2 replicates 2 times per day (separated by a minimum of 2 hours) for a total of 20 testing days.

The total imprecision across lots and instrument systems for the ARCHITECT HBsAg Qualitative assay was

- 2.1 to 2.9 %CV for the positive control
- 2.3 to 3.3 %CV for the low positive panel
- 2.2 to 2.9 %CV for the moderate positive panel, and
- The SD was 0.025 to 0.033 S/CO for the high negative panel

The results are summarized in the following table.

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Table 1: ARCHITECT HBsAg Qualitative Within-Laboratory Precision (20-Day) S/CO Results

| Instrument | Reagent Lot | Sample Level | n | Mean (S/CO) | Within-Run | | Within-Laboratory Precision (Total)* | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| i 2000_{SR} (1) | 1 | Negative Control | 118 | 0.18 | SD | %CV | SD | %CV |
| | | Positive Control | 119 | 3.45 | 0.059 | 1.7 | 0.095 | 2.7 |
| | | High Negative Panel | 119 | 0.77 | 0.022 | 2.9 | 0.033 | 4.3 |
| | | Low Positive Panel | 119 | 1.27 | 0.028 | 2.2 | 0.039 | 3.1 |
| | | Moderate Positive Panel | 118 | 3.63 | 0.071 | 1.9 | 0.093 | 2.6 |
| | 2 | Negative Control | 120 | 0.17 | 0.015 | NA | 0.030 | NA |
| | | Positive Control | 119 | 3.44 | 0.068 | 2.0 | 0.099 | 2.9 |
| | | High Negative Panel | 119 | 0.75 | 0.023 | 3.1 | 0.031 | 4.2 |
| | | Low Positive Panel | 119 | 1.25 | 0.031 | 2.4 | 0.040 | 3.2 |
| | | Moderate Positive Panel | 120 | 3.57 | 0.074 | 2.1 | 0.103 | 2.9 |
| | 3 | Negative Control | 120 | 0.15 | 0.012 | NA | 0.021 | NA |
| | | Positive Control | 120 | 3.31 | 0.063 | 1.9 | 0.084 | 2.5 |
| | | High Negative Panel | 120 | 0.72 | 0.023 | 3.2 | 0.031 | 4.4 |
| | | Low Positive Panel | 120 | 1.20 | 0.032 | 2.7 | 0.039 | 3.3 |
| | | Moderate Positive Panel | 120 | 3.40 | 0.060 | 1.8 | 0.088 | 2.6 |

* Total variability contains within-run, between-run, and between-day variance components.

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Table 1(Continued)
ARCHITECT HBsAg Qualitative Within-Laboratory Precision (20-Day)
S/CO Results

| Instrument | Reagent Lot | Sample Level | n | Mean (S/CO) | Within-Run | Within-Laboratory Precision (Total)* |
| --- | --- | --- | --- | --- | --- | --- |
| i 2000_{SR} (2) | 1 | Negative Control | 119 | 0.17 | 0.012 | NA | 0.017 | NA |
| Positive Control | 120 | 3.43 | 0.063 | 1.8 | 0.088 | 2.5 |
| High Negative Panel | 120 | 0.75 | 0.023 | 3.0 | 0.025 | 3.3 |
| Low Positive Panel | 120 | 1.26 | 0.026 | 2.1 | 0.029 | 2.3 |
| Moderate Positive Panel | 119 | 3.61 | 0.066 | 1.8 | 0.082 | 2.3 |
| 2 | Negative Control | 120 | 0.16 | 0.012 | NA | 0.016 | NA |
| Positive Control | 120 | 3.43 | 0.059 | 1.7 | 0.086 | 2.5 |
| High Negative Panel | 119 | 0.73 | 0.024 | 3.2 | 0.025 | 3.4 |
| Low Positive Panel | 119 | 1.23 | 0.029 | 2.4 | 0.033 | 2.7 |
| Moderate Positive Panel | 120 | 3.54 | 0.070 | 2.0 | 0.087 | 2.5 |
| 3 | Negative Control | 119 | 0.15 | 0.012 | NA | 0.014 | NA |
| Positive Control | 120 | 3.38 | 0.056 | 1.7 | 0.072 | 2.1 |
| High Negative Panel | 120 | 0.72 | 0.021 | 2.9 | 0.027 | 3.7 |
| Low Positive Panel | 119 | 1.22 | 0.032 | 2.7 | 0.038 | 3.1 |
| Moderate Positive Panel | 120 | 3.47 | 0.063 | 1.8 | 0.075 | 2.2 |
| i 2000 | 1 | Negative Control | 120 | 0.17 | 0.014 | NA | 0.025 | NA |
| Positive Control | 120 | 3.28 | 0.073 | 2.2 | 0.077 | 2.3 |
| High Negative Panel | 120 | 0.73 | 0.022 | 3.1 | 0.029 | 3.9 |
| Low Positive Panel | 120 | 1.21 | 0.030 | 2.5 | 0.035 | 2.9 |
| Moderate Positive Panel | 120 | 3.42 | 0.082 | 2.4 | 0.098 | 2.9 |

* Total variability contains within-run, between-run, and between-day variance components.

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# Seroconversion Sensitivity

A study was conducted to evaluate the seroconversion detection of the ARCHITECT HBsAg Qualitative assay and confirmation by the ARCHITECT HBsAg Qualitative Confirmatory assay. Thirty-eight (38) seroconversion panel sets of serial bleed panel members were tested using the ARCHITECT HBsAg Qualitative assay and confirmed (as warranted) using the ARCHITECT HBsAg Qualitative Confirmatory assay. The results were compared to the comparator HBsAg and HBsAg confirmatory results.

HBsAg was first detected by the ARCHITECT HBsAg Qualitative assay and confirmed by the ARCHITECT HBsAg Qualitative Confirmatory assay 2 to 15 days earlier than it was first detected by the comparator HBsAg assay in 17 seroconversion panel sets and coincident with the first day detected by the comparator HBsAg assay in 21 seroconversion panel sets.

A comparison of the number of days to reactive result for the ARCHITECT HBsAg Qualitative assay to the comparator HBsAg assay is presented in the following Table.

Table 2: Seroconversion Sensitivity
Days to First HBsAg Reactive Result
ARCHITECT HBsAg Qualitative and Confirmatory and
Comparator HBsAg and Confirmatory

| Panel ID | Days to HBsAg Reactive Result from Initial Draw Date | | Difference in Days to HBsAg Reactive Result (Comparator – ARCHITECT) |
| --- | --- | --- | --- |
| | Comparator HBsAg | ARCHITECT HBsAg Qualitative | |
| PHM909 | 9 | 9 | 0 |
| PHM917 | 43 | 36 | 7 |
| PHM925 | 8 | 4 | 4 |
| PHM926 | 13 | 9 | 4 |
| PHM927 | 4 | 4 | 0 |
| PHM928 | 9 | 7 | 2 |
| PHM929 | 18 | 14 | 4 |
| PHM930 | 3 | 3 | 0 |
| PHM933 | 7 | 7 | 0 |
| PHM934 | 0 | 0 | 0 |
| PHM935B | 128 | 128 | 0 |
| PHM935A(M2) | 21 | 21 | 0 |
| 26982/14399 | 3 | 3 | 0 |
| 13867/3482 | 19 | 19 | 0 |
| 1807/3463 | 11 | 11 | 0 |

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| 26022/14518 | 12 | 12 | 0 |
| --- | --- | --- | --- |
| 0994/3457 | 11 | 4 | 7 |
| 43527/3453 | 13 | 13 | 0 |
| 6271 | 7 | 7 | 0 |
| 6272 | 101 | 94 | 7 |
| 6273 | 25 | 25 | 0 |
| 6274 | 4 | 0 | 4 |
| 6275 | 22 | 7 | 15 |
| 11000 | 26 | 21 | 5 |
| 11001 | 44 | 44 | 0 |
| 11002 | 9 | 7 | 2 |
| 11003 | 142 | 142 | 0 |
| 11005 | 142 | 142 | 0 |
| 11006 | 51 | 42 | 9 |
| 11007 | 43 | 34 | 9 |
| 11008 | 72 | 69 | 3 |
| 11009 | 86 | 79 | 7 |
| 11011 | 110 | 103 | 7 |
| 11012 | 18 | 18 | 0 |
| 11013 | 252 | 247 | 5 |
| 11014 | 51 | 51 | 0 |
| 11016 | 27 | 27 | 0 |
| 11017 | 42 | 42 | 0 |

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## Analytical Sensitivity (Detectable Concentration at the Assay Cutoff)

The ARCHITECT HBsAg Qualitative assay is designed to have a mean analytical sensitivity value of less than or equal to 0.20 ng/mL (0.036 IU/mL). Analytical sensitivity was evaluated using serial dilutions of the WHO 2nd International HBsAg Standard (subtype adw2, genotype A, NIBSC Code 00/588).

The dilutions ranged from 0.01 to 0.50 IU/mL. HBsAg negative normal human serum or plasma was used as the diluent and represented the 0.00 IU/mL sample. The dilutions were tested across 3 reagent lots on 3 ARCHITECT instruments (2 i 2000SR and 1 i 2000). The analytical sensitivity for ARCHITECT HBsAg Qualitative ranged from 0.017 to 0.022 IU/mL across the instruments.

In the analytical sensitivity study, the observed limit of detection (LoD), calculated per NCCLS document EP17-A, was less than or equal to 0.002 IU/mL across the instruments.

## Genotype Detection

A study was performed to evaluate the ability of the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays to detect and confirm HBV genotypes A through H by testing a total of 19 genotype panel members.

HBV genotypes A through H were reactive by the ARCHITECT HBsAg Qualitative assay and confirmed positive by the ARCHITECT HBsAg Qualitative Confirmatory assay.

## Mutant Detection

A study was performed to evaluate the ability of the ARCHITECT HBsAg Qualitative assay to detect HBsAg mutants. Each member of a panel of 9 HBsAg recombinant proteins containing defined mutations between amino acid positions 122 and 145 was diluted with recalcified negative human plasma to an S/CO of 2.0 ± 0.5. The panel was tested using the ARCHITECT HBsAg Qualitative assay.

All nine mutant samples were repeatedly reactive by ARCHITECT HBsAg Qualitative. The ARCHITECT HBsAg Qualitative assay demonstrated the ability to detect (as reactive) the HBsAg mutant Thr-123-Ala and to have the ability to detect (as reactive) other HBsAg mutants (including Gly-145-Arg) when compared to the comparator HBsAg assay.

## Neonate Serum Evaluation

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A study was conducted to characterize the performance of the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays with neonate serum. Cord blood serum was used as a surrogate for neonate serum. A minimum of 20 cord blood specimens and matched maternal serum specimens that were negative for HBsAg and anti-HBs activity were obtained. Each specimen was divided into two aliquots. A high negative sample (target: 0.80 S/CO) was prepared for one aliquot; a low positive sample (target: 1.20 S/CO) was prepared from the other aliquot. The high negative and low positive samples were tested using the ARCHITECT HBsAg Qualitative assay. The low positive samples were tested using the ARCHITECT HBsAg Qualitative Confirmatory assay.

For the ARCHITECT HBsAg Qualitative assay, each cord blood sample was compared to the corresponding maternal sample. For the high negative sample, the mean difference between the cord blood sample and the matched maternal sample was 0.04 S/CO with an upper one-sided 95% confidence limit of 0.05 S/CO. For the low positive sample, the mean percent difference between the cord blood sample and the matched maternal sample, was 3.1% with a lower one-sided 95% confidence limit of 1.5%.

All low positive samples were confirmed positive by the ARCHITECT HBsAg Qualitative Confirmatory assay.

This study supports the use of ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays with neonate serum.

## Interferences – Bilirubin, Hemoglobin, Total Protein, and Triglycerides

A study was conducted to evaluate the susceptibility of the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays to potentially interfering substances based on guidance from the CLSI document EP7-A2.

At the concentrations listed below, the upper 95% confidence limits for the interferences from unconjugated bilirubin, conjugated bilirubin, hemoglobin, total protein, and triglycerides in the ARCHITECT HBsAg Qualitative assay were less than or equal to 0.15 S/CO shift for high negative samples and the lower 95% confidence limits were greater than or equal to -15% for low positive samples:

- Unconjugated bilirubin up to and including 20 mg/dL
- Conjugated bilirubin up to and including 20 mg/dL
- Hemoglobin up to and including 500 mg/dL
- Protein up to and including 12 g/dL
- Triglycerides up to and including 3000 mg/dL

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# Analytical Specificity – Medical Conditions and Other Disease States

The ARCHITECT HBsAg Qualitative assay was evaluated for potential cross-reactivity for specimens from individuals with other medical conditions. A list of the potential cross reactants tested and the results of the testing is presented in the following table.

Table 3: Cross Reactivity Study for the ARCHITECT HBsAg Qualitative and Confirmatory and Comparator HBsAg and Confirmatory

| Category | N | Comparator HBsAg Assay | | | |
| --- | --- | --- | --- | --- | --- |
| | | Negative/Not Confirmed | | Positive a | |
| | | ARCHITECT HBsAg Qualitative | | ARCHITECT HBsAg Qualitative | |
| | | Nonreactive | Reactive | Nonreactive | Reactive |
| Anti-nuclear antibodies (ANA) | 10 | 10 | 0 | 0 | 0 |
| Auto-immune hepatitis | 10 | 10 | 0 | 0 | 0 |
| C. trachomatis | 7 | 7 | 0 | 0 | 0 |
| Cytomegalovirus (CMV) | 10 | 10 | 0 | 0 | 0 |
| Epstein-Barr virus (EBV) | 10 | 10 | 0 | 0 | 0 |
| Fatty liver disease | 10 | 10 | 0 | 0 | 0 |
| Hemodialysis patient | 10 | 10 | 0 | 0 | 0 |
| Hepatitis A virus (HAV) | 10 | 10 | 0 | 0 | 0 |
| Hepatitis C virus (HCV) | 10 | 10 | 0 | 0 | 0 |
| Hepatocellular carcinoma | 10 | 10 | 0 | 0 | 0 |
| Herpes simplex virus (HSV) | 10 | 10 | 0 | 0 | 0 |
| HIV-1 | 10 | 10 | 0 | 0 | 0 |
| HIV-2 | 17 | 14 | 0 | 0 | 3 |
| Human anti-mouse antibodies (HAMA) positive | 15 | 15 | 0 | 0 | 0 |
| Human T-lymphotropic virus (HTLV-1/2) | 9 | 9 | 0 | 0 | 0 |
| IgG monoclonal gammopathy | 10 | 10 | 0 | 0 | 0 |
| IgM monoclonal gammopathy | 10 | 10 | 0 | 0 | 0 |
| Influenza vaccine recipients | 10 | 10 | 0 | 0 | 0 |
| Multiparous pregnancies | 10 | 10 | 0 | 0 | 0 |
| Multiple myeloma | 10 | 10 | 0 | 0 | 0 |
| Multiple transfusion recipients | 10 | 10 | 0 | 0 | 0 |
| N. gonorrhea | 9 | 9 | 0 | 0 | 0 |

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| Pregnancy 1st trimester | 15 | 15 | 0 | 0 | 0 |
| --- | --- | --- | --- | --- | --- |
| Pregnancy 2nd trimester | 14 | 14 | 0 | 0 | 0 |
| Pregnancy 3rd trimester | 15 | 15 | 0 | 0 | 0 |
| Rheumatoid arthritis (RF) | 10 | 10 | 0 | 0 | 0 |
| T. cruzi | 10 | 10 | 0 | 0 | 0 |
| T. pallidum | 10 | 10 | 0 | 0 | 0 |

All specimens were observed to be nonreactive with both the ARCHITECT HBsAg Qualitative and comparator HBsAg assays except for three specimens in the HIV-2 category that were HBsAg confirmed positive with the ARCHITECT HBsAg Qualitative and HBsAg positive with the comparator HBsAg assay. No discordant results were observed in this study.

## Tube Type Interference

A study was conducted to evaluate which anticoagulants (blood collection tube types) are acceptable for use with the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays. The study was evaluated using samples from a minimum of 25 donors spiked with HBsAg positive stock to reach two analyte levels; high negative sample level of 0.8 S/CO (S/CO range: 0.60-0.99) and a low positive sample level of 1.2 S/CO (S/CO range 1.00- 1.40)

The data support the use of serum (including serum collected in serum separator tubes) and plasma collected in lithium heparin (including separator tubes), dipotassium EDTA, tripotassium EDTA, or sodium heparin in the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays. For all of these tube types the differences between the control tube type for the low positive samples was <15% and less than 0.15 S/CO for the high negative samples.

## Sample Stability of Serum and Plasma

A study was conducted to evaluate the sample storage temperatures and number of freeze/thaw cycles for each blood collection tube type acceptable for use with the ARCHITECT HBsAg assay.

The data demonstrate that human serum (including serum collected in serum separator tubes) or plasma collected in lithium heparin (including separator tubes), potassium EDTA, or sodium heparin tubes may be used with the ARCHITECT HBsAg Qualitative assay when:

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- Stored at 2 to 8°C for up to 6 days
- Stored at 15 to 30°C (room temperature) for up to 24 hours
- Subjected to up to 3 freeze/thaw cycles

Lithium heparin tube type may demonstrate higher S/CO values for low positive specimens after freeze/thaw.

## Sample On Board Stability

A study was conducted to evaluate samples when stored on the ARCHITECT i System (on board storage) and tested using the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays on one ARCHITECT i 2000 SR instrument.

The study was evaluated using negative samples spiked with HBsAg positive stock to reach two analyte levels; high negative sample level of 0.8 S/CO and a low positive sample level of 1.2 S/CO.

For the ARCHITECT HBsAg Qualitative Assay, the sample on board stability was acceptable if, when comparing samples stored on-board the instrument for > 3 hours to samples tested immediately upon loading on the instrument,

- the difference for the high negative sample was less than or equal to 0.15 S/CO
- the percent difference for the low positive sample was greater than or equal to -15%.

For the ARCHITECT HBsAg Qualitative Confirmatory Assay, the sample on board stability was acceptable if, when comparing the sample stored on-board the instrument for > 3 hours to the sample tested immediately upon loading on the instrument, there was no qualitative change on each low Positive Panel neutralized result.

For the ARCHITECT HBsAg Qualitative assay, the mean difference for the high negative sample is 0.02 S/CO, and the mean percent difference for the low positive sample is 5.7%. For the ARCHITECT HBsAg Qualitative Confirmatory assay, there were no qualitative changes to the low positive sample result interpretation.

The results support sample storage of up to 3 hours on board the ARCHITECT i System when tested using the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays.

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# Within-Assay Sample Carryover

A study was performed to evaluate the susceptibility of the ARCHITECT HBsAg Qualitative assay to within-assay sample carryover. Three replicates of wash buffer were tested to clear the system. A single replicate of an HBsAg negative sample was tested to serve as a sample that was not exposed to potential sample carryover (protected sample). This was followed by a single replicate of the HBsAg high positive sample (high sample, HBsAg concentration > 125,000 IU/mL), then by a single replicate of the HBsAg negative sample to serve as a sample exposed to potential sample carryover (unprotected sample). The sequence of wash buffer, protected negative sample, high sample, and unprotected negative sample was repeated an additional 11 times for a total of 12 iterations.

The difference between the unprotected negative sample mean and the protected negative sample mean was 0.10 S/CO for the ARCHITECT i 2000SR, demonstrating the ARCHITECT HBsAg Qualitative assay is not susceptible to within-assay sample carryover.

# High Dose Hook Effect

A study was performed to characterize the performance of the ARCHITECT HBsAg Qualitative assay when used to test specimens containing high levels of HBsAg that have the potential to cause a high dose hook effect. The study results also apply to the ARCHITECT HBsAg Qualitative Confirmatory assay since the microparticle, conjugate, and ancillary wash buffer reagents are identical between the two assays.

To perform the study two HBsAg-positive human plasma specimens with HBsAg concentrations of 3235 IU/mL and 53650 IU/mL were used as the positive stocks. Serial dilutions of the positive stock samples were prepared using recalcified HBsAg-negative human plasma. Each dilution level (undiluted through 1:100,000,000) and the recalcified HBsAg-negative human plasma were tested in a minimum of 12 replicates on one ARCHITECT i 2000SR instrument using one lot each of reagents, calibrators, and controls. The ARCHITECT HBsAg Qualitative assay was considered not susceptible to high dose hook effect if each positive stock tested at undiluted had a reactive result. Both of the positive stocks were reactive when tested undiluted.

The ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory interpretations are not impacted by high dose hook effect.

# Stability Studies

All performance studies were conducted using the ARCHITECT i 2000/i 2000SR

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Systems.

## ARCHITECT HBsAg Qualitative Reagent Developmental and Transport Simulation Stabilities

The developmental stability is an on-going study to establish the stability (expiration dating) of the ARCHITECT HBsAg Qualitative Reagents at the intended storage condition of 2 to 8°C and during on-board storage. Testing is performed on three lots of 100-test kit reagents and two lots of 500-test kit reagents.

In addition, the developmental stability includes the in-use condition. The in-use condition simulates customer use over time. In-use condition testing is performed on one lot of 100-test kit reagents.

The transport simulation study tests reagents after they have been subjected to potential ambient transport conditions. Transport simulation testing is performed on one lot of 100-test kit reagents.

The intended storage condition results provide evidence that the ARCHITECT HBsAg Qualitative Reagents will work as intended and will meet the specification performance requirements if given a shelf life of 8 months. The results generated for in use and on-board storage conditions also support 8 months of dating for ARCHITECT HBsAg Qualitative Reagents.

## ARCHITECT HBsAg Qualitative Confirmatory Reagent Developmental and Transport Simulation Stability Studies

The developmental stability is an on-going study to establish the stability (expiration dating) of the ARCHITECT HBsAg Qualitative Confirmatory Reagents at the intended storage condition of 2 to 8°C and during on-board storage. Testing is performed on three lots of reagents.

In addition, the developmental stability includes the in-use condition. The in-use condition simulates customer use over time. In-use condition testing is performed on one lot of 100-test kit reagents.

The transport simulation study tests reagents after they have been subjected to potential ambient transport conditions. Transport simulation testing is performed on one lot of 100-test kit reagents.

The intended storage condition results provide evidence that the ARCHITECT HBsAg Qualitative Confirmatory Reagents will work as intended and will meet the specification performance requirements if given a shelf life of 8 months. The

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results generated for in use and on-board storage conditions also support 8 months of dating for ARCHITECT HBsAg Qualitative Confirmatory Reagents.

## ARCHITECT HBsAg Qualitative Calibrator and Control Developmental and Transport Simulation Stability Studies

The developmental stability studies are on-going studies to establish the expiration dating of the ARCHITECT HBsAg Qualitative Calibrators and Controls at the intended storage condition of 2 to 8°C. Intended storage stability testing is performed on three lots each of calibrators and controls.

In addition, the calibrator and control developmental stability includes the in-use condition. The in-use condition for the calibrators and controls simulates customer use over time. In-use condition testing is performed using one lot each of calibrators and controls.

The transport simulation study tests calibrators and controls after they have been subjected to potential ambient transport conditions. Transport simulation condition testing is performed using one lot each of calibrators and controls.

The intended storage condition results provide evidence that the ARCHITECT HBsAg Qualitative Calibrators and Controls will work as intended and will meet the specification performance requirements if given a shelf life of 8 months. The results generated for in use condition also support 8 months of dating for ARCHITECT HBsAg Qualitative Calibrators and Controls.

## ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent Recommended Storage Stability

The ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent has the same formulation as the ARCHITECT HBsAg Qualitative Negative Control. Therefore, the data used to support the stability of the ARCHITECT HBsAg Qualitative Negative Control are also used to support the stability of the ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent.

## Reagent On Board Evaluation

A study was performed to evaluate the performance of the ARCHITECT HBsAg Qualitative reagents when stored on board the ARCHITECT i 2000SR while the instrument was in continuous running mode (on board evaluation). A minimum of 17 time points were performed over at least a 31-day period.

Two controls and three panels were tested as follows:

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- Negative Control
- Positive Control
- High negative panel with a target S/CO value of 0.80
- Low positive panel with a target S/CO value of 1.20
- Moderate positive (release) panel with a target S/CO value of 3.50

The reagent on board evaluation for the ARCHITECT HBsAg Qualitative assay was considered acceptable if the shift from baseline over the course of 30 days was

- < + 0.15 S/CO for the high negative panel
- > -15% for the positive control and low positive and release panels

Across all instruments, the test mean percent shifts ranged from -4.5% to 3.8% for the positive control, -3.2% to 3.0% for the low positive panel, and -3.3% to 2.8% for the release panel. The test mean S/CO shifts ranged from 0.00 S/CO to 0.02 S/CO for the negative control and -0.03 S/CO to 0.04 S/CO for the high negative panel. The reference mean percent shifts ranged from -3.2% to 1.8% for the positive control, -4.3% to -0.4% for the low positive panel, and -5.5% to -1.5% for the release panel. The reference mean S/CO shifts ranged from -0.01 to 0.06 S/CO for the negative control and -0.04 S/CO to 0.04 S/CO for the high negative panel.

The results support a 30 day reagent storage of the ARCHITECT HBsAg Qualitative reagent kit on board the ARCHITECT i System while the instrument is in continuous running mode.

## Microbial Challenge Characterization

A Microbial Challenge Characterization (MCC) evaluation was performed for the ARCHITECT HBsAg Qualitative reagents, Calibrator, and Controls and ARCHITECT HBsAg Qualitative Confirmatory reagents. The MCC consisted of an Antimicrobial Effectiveness Testing (AET) evaluation and a Microbial Interference Characterization (MIC) evaluation. The MCC evaluation integrated the results from both AET and MIC, to determine that the product is adequately protected.

The AET evaluation was performed to establish the level of antimicrobial protection provided by the preservative formulation of the ARCHITECT HBsAg Qualitative Reagents, Calibrators, and Controls and the ARCHITECT HBsAg

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Qualitative Confirmatory Reagents and Manual Diluent. The ARCHITECT HBsAg Qualitative Calibrator 2 (LN 4P53Q-01) and the ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent (LN 4P54P-01) have the same formulation as the ARCHITECT HBsAg Qualitative Negative Control (LN 4P53L-01). Therefore, the results used to support the AET stability of the ARCHITECT HBsAg Qualitative Negative Control can be used to support the AET stability of the ARCHITECT HBsAg Qualitative Calibrator 2 and ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent.

The AET testing was performed per Abbott’s procedures and based on guidance from the U.S. Pharmacopeia-National Formulary (USP-NF) General Chapter 51, Antimicrobial Effectiveness Test, to determine the concentrations and types of microbial organisms inoculated and evaluated in the test.

The AET test results classified the materials tested into three groups based on the observed microbial counts displayed. The groups were cidal, static or neither static or cidal. For all of the materials tested, the results were cidal for all microbial groups that were evaluated. For each study, the reference conditions for each on-test material showed no evidence of microbial growth throughout the study.

The MIC evaluation was performed to demonstrate the effect of the microbial bioburden and/or its by-products on the assay performance of the ARCHITECT HBsAg Qualitative Reagent. The on-test materials and their antimicrobial formulations were selected based on Abbott’s procedures.

The ARCHITECT HBsAg Qualitative Reagents were considered not sensitive to a bioburden level of 103 to 104 CFU/mL if: for the positive control and each panel, the percent difference point estimate in S/CO units between the reference and test conditions was greater or equal to -15%, for the negative control, when each inoculated replicate S/CO was less than or equal to 0.85, and the difference of the test condition mean S/CO was less than or equal to +0.15 S/CO from the reference condition mean S/CO. If the above criteria were not met, the ARCHITECT HBsAg Qualitative Reagents were considered sensitive to the bioburden level tested.

All individual negative control S/CO results were < 0.27 S/CO. The difference in negative control mean S/CO ranged from -0.01 to 0.01 S/CO. The positive control percent differences ranged from -2.1% to 1.6%. The ARCHITECT HBsAg Qualitative Reagents were not sensitive to any microbial organisms when inoculated at 103 to 104 CFU/mL.

The overall conclusion of the MCC evaluation indicated that the level of

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antimicrobial protection provided by the preservative formulation for ARCHITECT HBsAg Qualitative Reagents, Calibrators, and Controls and ARCHITECT HBsAg Qualitative Confirmatory Reagents is adequate. In addition, the MCC results for the Negative Control apply to the ARCHITECT HBsAg Qualitative Calibrator 2 and ARCHITECT HBsAg Qualitative Confirmatory Manual Diluent.

## X. SUMMARY OF CLINICAL STUDIES

A prospective multi-center study was conducted to evaluate the precision of the ARCHITECT HBsAg Qualitative assay and the agreement between the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays and a comparator HBsAg/HBsAg confirmatory assay using clinical specimens from the intended use diagnostic populations.

There were no adverse device events during the clinical investigation. The study was conducted at three clinical testing sites.

### System Reproducibility (5-Day Precision)

A study was conducted to validate the precision performance of the ARCHITECT HBsAg Qualitative assay based on guidance from the NCCLS document EP5-A2 and CLSI document EP15-A2. Three lots each of ARCHITECT HBsAg Qualitative Reagents, Calibrators, and Controls were tested at each of three clinical testing sites. The ARCHITECT HBsAg Qualitative Negative Control and Positive Control, a high negative panel member (targeted to 0.80 S/CO), a low positive panel member (targeted to 1.20 S/CO), and a moderate positive panel member (targeted to 3.50 S/CO) were assayed in replicates of four at two separate times per day for five days. The results are presented in the following table

Table 4
ARCHITECT HBsAg Qualitative System Reproducibility (5-Day Precision)
All Sites, All Reagent Lots

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ARCHITECT i 2000/i 2000SR

| Sample | n | Grand Mean S/CO | Within-Run | | Within-Day | | Within-Laboratory Precision (Total)^{a} | | Precision with Additional Component of Between-Site^{b} | | Precision with Additional Component of Between-Lot^{b} | | Precision with Additional Components of Site and Lot (Overall)^{b} | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Negative Control | 360 | 0.17 | 0.028 | NA | 0.031 | NA | 0.031 | NA | 0.034 | NA | 0.034 | NA | 0.035 | NA |
| Positive Control | 360 | 3.45 | 0.066 | 1.9 | 0.070 | 2.0 | 0.073 | 2.1 | 0.087 | 2.5 | 0.137 | 4.0 | 0.137 | 4.0 |
| High Negative | 360 | 0.77 | 0.037 | 4.8 | 0.061 | 7.9 | 0.061 | 7.9 | 0.063 | 8.3 | 0.061 | 7.9 | 0.063 | 8.3 |
| Low Positive | 360 | 1.28 | 0.066 | 5.1 | 0.066 | 5.1 | 0.066 | 5.1 | 0.069 | 5.4 | 0.075 | 5.9 | 0.075 | 5.9 |
| Moderate Positive | 360 | 3.64 | 0.134 | 3.7 | 0.138 | 3.8 | 0.138 | 3.8 | 0.153 | 4.2 | 0.188 | 5.2 | 0.188 | 5.2 |

a Total variability contains within-run, between-run, and between-day variance components.
b Includes the lot-site interaction component.

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Expected Results and Method Comparison

## Description of Patient Population

Of the 2800 specimens tested and analyzed in the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory clinical study, 1279 specimens were from individuals at increased risk of HBV infection due to lifestyle, behavior, occupation, or known exposure event; 675 specimens were from individuals with signs and symptoms of hepatitis infection; 8 specimens were from subjects with clinically diagnosed acute HBV infection; 67 specimens were from subjects with clinically diagnosed chronic infection defined by the presence of HBsAg for >= 6 months; 29 specimens were classified as based on four-marker HBV reference testing; 22 specimens were classified as chronic based on four-marker HBV reference testing; and 720 specimens were from pregnant females.

## Study Design

Each specimen was tested using the ARCHITECT HBsAg Qualitative assay and, if warranted, the ARCHITECT HBsAg Qualitative Confirmatory assay at one of the three clinical testing sites. Each specimen was also tested with the HBsAg and HBsAg confirmatory (where required) comparator methods at a reference laboratory.

Specimens from the increased risk of HBV infection, signs and symptoms of hepatitis infection, and acute and chronic HBV infection populations were also tested with three HBV reference assays, each detecting a unique serological marker (anti-HBc IgM, total anti-HBc, and anti-HBs). HBV classification was based on the reference marker patterns presented in Table 5. The classification used was a modification of the National Centers of Infectious Diseases of the Centers for Disease Control and Prevention (CDC) interpretation of Viral Hepatitis B Panel testing.

Supplemental testing was performed for specimen results that were discordant between the ARCHITECT HBsAg Qualitative and ARCHITECT HBsAg Qualitative Confirmatory assays and the comparator HBsAg and HBsAg confirmatory assays to better characterize the specimen.

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Table 5: HBV Classification

| HBV Reference Markers | | | | HBV Classification |
| --- | --- | --- | --- | --- |
| HBsAg | Anti-HBc IgM | Total Anti-HBc | Anti-HBs | |
| + | – | – | – | Acute |
| + | I | + | – | Acute |
| + | + | + | – | Acute |
| + | – | + | – | Chronic |
| + | – | + | + | Chronic |
| + | – | – | + | Chronic |
| + | + | + | + | Late acute/recovering^{a} |
| – | + | + | + | Recovering acute |
| – | + | + | – | Recovering acute/undetectable HBsAg |
| – | + | – | + | Recovering acute |
| – | + | – | – | Possible recovering acute, |
| – | I | + | + | Distantly immune |
| – | I | + | – | Possible distantly immune, anti-HBs not |
| – | – | + | – | Distantly immune, anti-HBs not detected |
| – | – | + | + | Immune due to natural infection |
| – | – | – | + | Immune due to HBV vaccination |
| – | – | – | – | Susceptible |

• + = Positive/Reactive; – = Negative; I = Indeterminate
^a One additional marker pattern was observed during the clinical study.

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Expected Results

# Increased Risk of HBV Infection Population

Of the 2800 specimens tested in the ARCHITECT HBsAg Qualitative clinical study, 1279 specimens were from individuals with increased risk of HBV infection. All 1279 individuals were at risk for HBV infection due to lifestyle, behavior, occupation, or a known exposure event but were asymptomatic and reported no current signs or symptoms of hepatitis.

The increased risk population (n=1279) consisted of the following race/ ethnic groups: 598 (46.76%) Caucasian, 470 (36.75%) African American, 159 (12.43%) Hispanic, 25 (1.95%) Asian, 2 (0.16%) American Indian/Alaska Native, and 25 (1.95%) were from other ethnic groups. Samples were collected from geographically diverse locations within the US.

The distribution of ARCHITECT HBsAg Qualitative results by age group and gender for the increased risk of HBV infection population is presented in the following table.

Table 6: Assay Results by Age Range and Gender Individuals at Increased Risk of HBV Infection

| Age Range (Years) | Gender | ARCHITECT HBsAg Qualitative Result | | Total |
| --- | --- | --- | --- | --- |
| | | Number of Reactive (%) | Number of Nonreactive (%) | |
| 10 to 19 | Female | 1 (7.69) | 12 (92.31) | 13 |
| | Male | 2 (18.18) | 9 (81.82) | 11 |
| 20 to 29 | Female | 2 (1.12) | 176 (98.88) | 178 |
| | Male | 2 (1.36) | 145 (98.64) | 147 |
| 30 to 39 | Female | 3 (2.65) | 110 (97.35) | 113 |
| | Male | 8 (4.71) | 162 (95.29) | 170 |
| 40 to 49 | Female | 1 (0.63) | 159 (99.38) | 160 |
| | Male | 4 (1.90) | 206 (98.10) | 210 |
| 50 to 59 | Female | 5 (5.05) | 94 (94.95) | 99 |
| | Male | 12 (11.21) | 95 (88.79) | 107 |
| 60 to 69 | Female | 4 (11.11) | 32 (88.89) | 36 |
| | Male | 0 (0.00) | 17 (100.00) | 17 |
| 70 to 79 | Female | 0 (0.00) | 5 (100.00) | 5 |
| | Male | 0 (0.00) | 9 (100.00) | 9 |
| 80 to 89 | Female | 0 (0.00) | 2 (100.00) | 2 |
| | Male | 0 (0.00) | 0 (0.00) | 0 |
| Unknown | Female | 0 (0.00) | 1 (100.00) | 1 |
| | Male | 0 (0.00) | 1 (100.00) | 1 |
| Total | | 44 (3.44) | 1235 (96.56) | 1279 |

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Results – ARCHITECT HBsAg Qualitative

# Increased Risk of HBV Infection and Signs and Symptoms of Hepatitis Infection Populations

Of the 2800 specimens tested and analyzed, 1954 specimens were from individuals at increased risk of HBV infection and signs and symptoms of hepatitis infection populations.

Specimens (n=1954) from these populations consisted of the race/ethnic groups: 970 (49.64%) Caucasian, 598 (30.60%) African American, 311 (15.92%) Hispanic, 40 (2.05%) Asian, 5 (0.26%) American Indian/Alaska Native, 30 (1.54%) Other.

The positive percent agreement between the ARCHITECT HBsAg Qualitative assay results and the comparator HBsAg assay final interpretation for the increased risk of HBV infection and signs and symptoms of hepatitis infection populations combined was 97.83% (90/92) with a 95% exact confidence interval of 92.37% to 99.74% while the negative percent agreement was 99.30% (1849/1862) with a 95% exact confidence interval of 98.81% to 99.63%.

The negative percent agreement and positive percent agreement results for the increased risk of HBV infection and signs and symptoms of hepatitis infection populations by HBV classification are presented in the following table.

Table 7
Percent Agreement by HBV Classification
Individuals at Increased Risk of HBV Infection and Individuals with Signs and Symptoms of Hepatitis Infection
ARCHITECT HBsAg Qualitative Interpretation and Comparator HBsAg Final Interpretation
N = 1954

| HBV Classification | Positive Percent Agreement (%) | 95% Confidence Interval (%) | Negative Percent Agreement (%) | 95% Confidence Interval (%) |
| --- | --- | --- | --- | --- |
| Acute | 100.00 (7/7) | (59.04, 100.00) | NA | NA |
| Chronic | 97.65 (83/85) | (91.76, 99.71) | NA | NA |
| Recovering Acute | NA | NA | 100.00 (9/9) | (66.37, 100.00) |
| Recovering Acute, Undetectable HBsAg | NA | NA | 100.00 (3/3) | (29.24, 100.00) |
| Distantly Immune, Anti-HBs Not Detected | NA | NA | 97.44 (114/117) | (92.69, 99.47) |
| Immune Due to Natural Infection | NA | NA | 98.21 (219/223) | (95.47, 99.51) |
| Immune Due to HBV Vaccination | NA | NA | 100.00 (414/414) | (99.11, 100.00) |
| Susceptible | NA | NA | 99.45 (1090/1096) | (98.81, 99.80) |
| Total | 97.83 (90/92) | (92.37, 99.74) | 99.30 (1849/1862) | (98.81, 99.63) |

NA = Not Applicable

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# Acute and Chronic HBV Infection Populations

Of the 2800 specimens tested and analyzed, 126 were from pre-selected specimens from individuals with acute and chronic HBV infection.

The percent agreement between the ARCHITECT HBsAg Qualitative assay results and the comparator HBsAg assay final interpretation for the individuals with acute and chronic HBV infection is presented in the following table.

Table 8: Percent Agreement Individuals with Acute or Chronic HBV Infection ARCHITECT HBsAg Qualitative Interpretation and Comparator HBsAg Final Interpretation

| Specimen Category | Positive Percent Agreement (%) | 95% Confidence Interval (%) | Negative Percent Agreement (%) | 95% Confidence Interval (%) |
| --- | --- | --- | --- | --- |
| Individuals with Acute HBV Infection | 97.30 (36/37) | (85.84, 99.93) | NA | NA |
| Individuals with Chronic HBV Infection | 100.00 (86/86) | (95.80, 100.00) | 66.67 (2/3) | (9.43, 99.16) |
| Total | 99.19 (122/123) | (95.55, 99.98) | 66.67 (2/3) | (9.43, 99.16) |

NA = Not Applicable

# Comparison of Results

The ARCHITECT HBsAg Qualitative assay results were compared with the comparator HBsAg assay final interpretation for each of the HBV classifications for the increased risk of HBV infection and signs and symptoms of hepatitis infection populations (n = 1954) and the acute or chronic HBV infection populations (n=126). The results are presented in the following table.

Table 9: Comparison of Results Individuals at Increased Risk of HBV Infection and Signs and Symptoms of Hepatitis Infection ARCHITECT HBsAg Qualitative Interpretation and Comparator HBsAg Final Interpretation

| HBV Classification | Comparator HBsAg Final Interpretation | Total |
| --- | --- | --- |
| Confirmed Positive * | Negative/Not Confirmed |
| ARCHITECT HBsAg Qualitative Result | ARCHITECT HBsAg Qualitative Result |
| Reactive | Nonreactive | Reactive | Nonreactive |
| N | N | N | N | N |
| Acute | 47 | 1 | 0 | 0 | 48 |
| Chronic | 160 | 2 | 0 | 0 | 162 |
| Late Acute, Recovering | 5 | 0 | 0 | 0 | 5 |

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| Recovering Acute | 0 | 0 | 0 | 9 | 9 |
| --- | --- | --- | --- | --- | --- |
| Recovering Acute, Undetectable HBsAg | 0 | 0 | 0 | 3 | 3 |
| Distantly Immune, Anti-HBs Not Detected | 0 | 0 | 3 | 115 | 118 |
| Immune Due to Natural Infection | 0 | 0 | 5 | 220 | 225 |
| Immune Due to HBV Vaccination | 0 | 0 | 0 | 414 | 414 |
| Susceptible | 0 | 0 | 6 | 1090 | 1096 |
| Total | 212 | 3^{b} | 14^{c} | 1851 | 2080 |

a The comparator HBsAg final positive interpretation includes retesting and confirmatory testing according to the comparator package inserts.
b All 3 specimens were positive for an additional marker (anti HBc, or anti-HBs) or had DNA present (assay sensitivity of 169 copies/mL).
c Of these 14 specimens, 1 specimen was not confirmed on the ARCHITECT HBsAg Qualitative Confirmatory assay, 10 specimens were positive for an additional marker (anti-HBc, anti HBs or anti-HBe) or had DNA present, and 3 specimens had no additional markers or DNA present.

## Increased Risk Population Testing

In addition to the 1279 specimens from individuals at increased risk tested at 3 clinical sites, 498 specimens from hemodialysis patients were tested at Abbott Laboratories. The following table compares the ARCHITECT HBsAg Qualitative results and comparator HBsAg assay final interpretations for each risk factor for this overall increased risk population. The results are presented in the following table.

Table 10: Increased Risk Population Testing
ARCHITECT HBsAg Qualitative Interpretation and
Comparator HBsAg Final Interpretation

| Specimen Category | Comparator HBsAg Assay Final Interpretation | | | | Total (N) |
| --- | --- | --- | --- | --- | --- |
| | Confirmed Positive | | Negative/Not Confirmed | | |
| | ARCHITECT HBsAg Qualitative Result | | ARCHITECT HBsAg Qualitative Result | | |
| | Reactive (N) | Nonreactive (N) | Reactive (N) | Nonreactive (N) | |
| Multiple Sex Partners | 23 | 1 | 3 | 876 | 903 |
| Injecting Drug User (IDU) | 2 | 0 | 1 | 116 | 119 |
| Men who have Sex with Men (MSM) | 1 | 0 | 1 | 9 | 11 |
| Sexual Contact with HBV | 2 | 0 | 0 | 22 | 24 |
| Household Contact with HBV | 6 | 0 | 0 | 43 | 49 |
| Occupational Exposure Incident | 2 | 0 | 1 | 163 | 166 |
| Hemodialysis Patient | 2 | 0 | 0 | 499 | 501^{a} |
| Perinatal Exposure to HBV | 2 | 0 | 0 | 2 | 4 |

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| Total | 40 | 1 | 6 | 1730 | 1777 |
| --- | --- | --- | --- | --- | --- |

* Of these 501 specimens, 3 specimens were tested at clinical sites and 498 specimens were tested at Abbott Laboratories.

## Pregnant Female Population

For the pregnant female population (n=720), the positive percent agreement was 100.00% (1/1) with a 95% confidence interval of 2.50% to 100.00% and the negative percent agreement was 100.00% (719/719) with a 95% confidence interval of 99.49% to 100.00% for the ARCHITECT HBsAg Qualitative interpretation versus the comparator HBsAg final interpretation.

The pregnant female population (n=720) consisted of the following race/ ethnic groups: 48 (6.67%) Caucasian, 74 (10.28%) African American, 573 (79.58%) Hispanic, 15 (2.08%) Asian, 2 (0.28%) American Indian/Alaska Native, and 8 (1.11%) from other ethnic groups.

## Pediatric Population

Of the 2800 specimens in the clinical study, 142 specimens were from a pediatric population aged 17 to 21. In addition, 68 specimens from pediatric individuals aged 4 to 18 who were at increased risk of HBV infection were tested at Abbott Laboratories.

The distribution of ARCHITECT HBsAg Qualitative reactive and nonreactive results by age range and gender is presented in the following table.

Table 12: Assay Results by Age Range and Gender Pediatric Specimens

| Age Range (Years) | Gender | ARCHITECT HBsAg Qualitative Result | | Total |
| --- | --- | --- | --- | --- |
| | | Reactive N (%) | Nonreactive N (%) | |
| >4 to 12 | Female | 1 (5.26) | 18 (94.74) | 19 |
| | Male | 0 (0.00) | 22 (100.00) | 22 |
| >12 to 18 | Female | 0 (0.00) | 23 (100.00) | 23 |
| | Male | 0 (0.00) | 7 (100.00) | 7 |
| >18 to 21 | Female | 2 (1.75) | 112 (98.25) | 114 |
| | Male | 3 (12.00) | 22 (88.00) | 25 |
| Total | | 6 (2.86) | 204 (97.14) | 210 |

For the pediatric specimens (n=210);

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The negative percent agreement NPA was 99.51% (203/204) with a 95% confidence interval of 97.30% to 99.99%

The positive percent agreement was 83.33% (5/6) with a 95% confidence interval of 35.88% to 99.58% for the ARCHITECT HBsAg Qualitative result versus the comparator HBsAg final interpretation.

## Results – ARCHITECT HBsAg Qualitative Confirmatory

Of the 2800 specimens tested in this study, 234 specimens were tested using the ARCHITECT HBsAg Qualitative Confirmatory assay and/or comparator HBsAg confirmatory assay. The results are presented by specimen category in the following table.

### Table 13: Comparison of Results by Specimen Category

#### ARCHITECT HBsAg Qualitative Confirmatory Interpretation and Comparator HBsAg Confirmatory Interpretation

| Specimen Category | Comparator HBsAg Confirmatory Interpretation | | | | Total |
| --- | --- | --- | --- | --- | --- |
| | Confirmed Positive a | | Negative/Not Confirmed | | |
| | ARCHITECT HBsAg
Qualitative Confirmatory
Interpretation | | ARCHITECT HBsAg
Qualitative Confirmatory
Interpretation | | |
| | Confirmed
Positive | Negative/
Not Confirmed | Confirmed
Positive | Negative/
Not Confirmed | |
| | N | N | N | N | N |
| Increased Risk of HBV Infection | 37 | 2 | 5 | 4 | 48 |
| Signs and Symptoms of Hepatitis
Infection | 52 | 1 | 7 | 1 | 61 |
| Individuals with Acute HBV
Infection | 36 | 1 | 0 | 0 | 37 |
| Individuals with Chronic HBV
Infection | 86 | 0 | 1 | 0 | 87 |
| Pregnant Females | 1 | 0 | 0 | 0 | 1 |
| Total | 212 | 4 | 13 | 5 | 234 |

a The comparator HBsAg final positive interpretation includes retesting and confirmatory testing according to the comparator package inserts.

Of the 234 specimens that required confirmation by either assay, 233 specimens from the increased risk of HBV infection, signs and symptoms of hepatitis infection, acute and chronic HBV infection populations were classified by HBV infection. The confirmatory results are presented by HBV classification in the following table.

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Table 14: Comparison of Results by HBV Classification
Individuals at Increased Risk of HBV Infection, Individuals with Signs and Symptoms of Hepatitis Infection,
and Individuals with Acute or Chronic HBV Infection
ARCHITECT HBsAg Qualitative Confirmatory Interpretation and
Comparator HBsAg Confirmatory Interpretation

| HBV Classification | Comparator HBsAg Confirmatory Interpretation | | | | Total |
| --- | --- | --- | --- | --- | --- |
| | Confirmed Positive a | | Negative/Not Confirmed | | |
| | ARCHITECT HBsAg Qualitative Confirmatory Interpretation | | ARCHITECT HBsAg Qualitative Confirmatory Interpretation | | |
| | Confirmed Positive | Negative/Not Confirmed | Confirmed Positive | Negative/Not Confirmed | |
| | N | N | N | N | N |
| Acute | 47 | 1 | 0 | 0 | 48 |
| Chronic | 159 | 3 | 0 | 0 | 162 |
| Late Acute, Recovering | 5 | 0 | 0 | 0 | 5 |
| Distantly Immune, Anti-HBs Not Detected | 0 | 0 | 3 | 1 | 4 |
| Immune Due to Natural Infection | 0 | 0 | 5 | 0 | 5 |
| Immune Due to HBV Vaccination | 0 | 0 | 0 | 1 | 1 |
| Susceptible | 0 | 0 | 5 | 3 | 8 |
| Total | 211 | 4 b | 13 c | 5 | 233 |

a The comparator HBsAg final positive interpretation includes retesting and confirmatory testing according to the comparator package inserts.
b All 4 specimens were positive for an additional marker (anti-HBc, or anti-HBs) or had DNA present (assay sensitivity of 169 copies/mL).
c Of these 13 specimens, 10 specimens were positive for an additional marker (anti-HBc, anti-HBs, or anti-HBe) or had DNA present and 3 specimens had no markers or DNA present.

# XI. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the FDA Microbiology Devices Advisory 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 NONCLINICAL AND CLINICAL STUDIES

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# A. Safety Conclusions

As an *in-vitro* diagnostic test the ARCHITECT HBsAg Qualitative and the ARCHITECT HBsAg Qualitative Confirmatory involve removal of blood from an individual for testing purposes. The test, therefore, presents no more safety hazard to an individual being tested than other tests where blood is drawn.

False positive and false negative results are discussed in Section VIII. There were no adverse effects of the device reported while the study was conducted.

# B. Effectiveness Conclusions

- The ARCHITECT HBsAg Qualitative and the ARCHITECT HBsAg Qualitative Confirmatory Assays demonstrated acceptable analytical sensitivity as determined by limit of detection studies comparing with the WHO International Standard and through seroconversion studies.
- The ARCHITECT HBsAg Qualitative precision around the assay cut-off and across the assay range was within acceptable limits (%CV less than 5% for internal repeatability and less than 10% for within laboratory reproducibility).
- The Assay demonstrated the analytical ability to detect all the HBV genotypes A through H and the ability to detect the HBsAg mutant Thr-123-Ala and other HBsAg mutants (including Gly-145-Arg) when compared to the comparator HBsAg assay.
- The analytical specificity studies showed that there are no concerns with endogenous interferents at physiological levels, or with potential cross reactive agents.
- The Assays demonstrated equivalent performance with serum and plasma samples.
- Sample stability with the ARCHITECT HBsAg Qualitative assays was demonstrated to be valid for up to 7 days (2-8°C) or for 24 hours at 15-30°C and can withstand 3 freeze/thaw cycles.
- The claimed reagent stability information was adequately substantiated by analytical study results. The real-time stability information provided supports a shelf life of 8 month when stored at 2-8°C.
- The clinical performance was evaluated in an ethnically diverse population representative of the intended use population and representative of the different HBV classification groups. The positive and negative percent agreement values for both the ARCHITECT HBsAg Qualitative and the ARCHITECT HBsAg Qualitative Confirmatory assays were acceptable.

# C. Overall Conclusions

The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the instructions for use. The submitted clinical studies have shown that the ARCHITECT HBsAg Qualitative and the ARCHITECT HBsAg Qualitative Confirmatory Assays, when compared to

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reference clinical laboratory procedures, has a similar ability to detect the presence of HBsAg in specimens from persons with signs and symptoms of hepatitis and in persons at risk for hepatitis B infection. The rate of false positivity and false negativity are within acceptable limits compared to the reference assay. It has been shown that the device has no demonstrable cross-reactivity with the majority of viruses or organisms that may cause clinical hepatitis. Therefore, this device should benefit the physician in the diagnosis and management of HBV.

## XIII. CDRH DECISION

CDRH issued an approval order on April 12, 2012.

The applicant’s manufacturing facilities were 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.

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