**Summary of Safety and Effectiveness Data**

I.  **GENERAL INFORMATION**

Device Generic Name: Reagent system for the measurement of

antibodies against hepatitis B surface

antigen

Device Trade Name: IMMULITE^^ Anti-HBs

> IMMULITE^^ 2000 Anti-HBs

Applicant's Name and Address: Diagnostic Products Corporation

> 5700 West 96^th^ Street

Los Angeles, California 90045-5597

Premarket Approval Application (PMA) Number: P010052

Date of Panel Recommendation: None

Date of Notice of Approval to the Applicant: July 22, 2002

II. **INDICATIONS FOR USE**

**IMMULITE Anti-HBs**

For *in vitro* diagnostic use with the IMMULITE automated immunoassay
analyzer for the qualitative measurement of total antibodies to the
hepatitis B surface antigen (anti-HBs) in human serum and plasma
(heparinized or 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.

**IMMULITE 2000 Anti-HBs**

For *in vitro* diagnostic use with the IMMULITE 2000 automated
immunoassay analyzer for the qualitative measurement of total antibodies
to the hepatitis B surface antigen (anti-HBs) in human serum and plasma
(heparinized or 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.

III. **DEVICE DESCRIPTION**

The IMMULITE and IMMULITE 2000 Anti-HBs kits are the subjects of this
PMA. Data are presented separately for each assay. Each assay has its
own package insert.

The IMMULITE and IMMULITE 2000 Anti-HBs kits are solid phase, two step
chemiluminescent enzyme immunoassays designed for use on the automated
IMMULITE and IMMULITE 2000 analyzers, for the qualitative measurement of
*antibodies against* *hepatitis B surface antigen* (HBsAg) in human
serum or plasma. The kits are intended for *in vitro* use as an aid in
the determination of immune status to the hepatitis B virus.

The kits' solid phase is a polystyrene bead coated with purified HBsAg
subtypes ad and ay. The patient sample and a protein-based buffer are
simultaneously introduced into the Test Unit and incubated for
approximately 30 minutes at 37 ^o^C with intermittent agitation. During
this time, antibodies to HBsAg in the patient sample bind to the
HBsAg-coated bead. Unbound serum is then removed by a centrifugal wash.
An alkaline phosphatase-labeled HBsAg is introduced, and the reaction
tube is incubated with agitation for another 30 minute cycle. The
unbound enzyme conjugate is removed by a centrifugal wash. After the
wash, a chemiluminescent substrate is added, and the reaction tube is
incubated with agitation for a further 5 -- 10 minutes.

The chemiluminescent substrate is a phosphate ester of adamantyl
dioxetane which undergoes hydrolysis in the presence of alkaline
phosphatase to yield an unstable intermediate. The continuous production
of this intermediate results in the sustained emission of light. The
bound complex and the resulting photon output, measured as cps by the
photomultiplier tube, are related to the presence of antibodies to HBsAg
in the sample.

IV. **[Contraindications, WARNINGS AND PRECAUTIONS]{.mark}**

[]{.mark}

[There are no known contraindications for the]{.mark} IMMULITE Anti-HBs
and IMMULITE 2000 Anti-HBs Immunoassay.

Warnings and precautions [for the]{.mark} IMMULITE Anti-HBs and IMMULITE
2000 Anti-HBs Immunoassays are stated in the device labeling.

V.  **ALTERNATIVE PRACTICES OR PROCEDURES**

Measuring antibodies against hepatitis B surface antigen in individuals
may be achieved by using a variety of commercially available, FDA
licensed or approved serological tests. Assays have been developed using
radioimmunoassay or enzyme immunoassay methodologies. When the test
results are used in combination with other serological markers expressed
during the three phases of incubation, the presence of hepatitis B virus
may be determined.

VI. **MARKETING HISTORY**

IMMULITE Anti-HBs and IMMULITE 2000 Anti-HBs have been marketed
internationally as an aid in the determination of acute and chronic
hepatitis B virus infection since July 1996. IMMULITE and IMMULITE 2000
Anti-HBs have received European Union CE Mark approval and have been
marketed in Europe since June 2001. The devices have not been withdrawn
from any country for reasons related to safety and effectiveness.

VII. **POTENTIAL ADVERSE EFFECTS OF DEVICE ON HEALTH**

As an *in vitro* diagnostic test system, there is no direct adverse
effect of IMMULITE and IMMULITE 2000 Anti-HBs assays on the health of
the patient. The possibility of erroneous test results due to test
malfunctions or operator errors exists. A false non-reactive result
would make the patients unnecessarily receive a vaccine, vaccine
booster, hyperimmune globulin, or be considered not to have recovered
from an HBV infection when in fact they have recovered.

A false reactive test result may be of concern to patients or the public
health because the patient is considered to be immune to natural HBV
infection or was successfully vaccinated. In this case, the risk is that
the patient would not receive a vaccine, vaccine booster, or hyperimmune
globulin, and would be at higher risk of infection if exposed to HBV.
Once exposed, the risk of this patient spreading infection to uninfected
or non-immune members of the community increases.

Blood specimens obtained from a subject infected with hepatitis B prior
to the appearance of an antibody titer have the potential to misdiagnose
the patient as not being infected. Additionally, specimens obtained
after the disappearance of anti-HBc IgM antibodies, in the absence of
test results for other hepatitis B markers, may lead to misdiagnosis of
a hepatitis B infected patient.

The risk of incorrect test results is inherent with all *in vitro*
diagnostic products. Therefore, the above potential risks are not
unusual in the laboratory setting. Appropriate warnings for each of
these risks are contained in the labeling and package insert
instructions. Standard good laboratory practices are considered
sufficient to minimize risks to the end user.

VIII. **SUMMARY OF NON CLINICAL STUDIES**

**Analytical Specificity**

Analytical specificity was evaluated at two clinical sites in the United
States and one European site. In the United States, serum specimens from
17 subgroups of patients with potentially cross-reacting microorganisms
or conditions were tested by IMMULITE Anti-HBs, IMMULITE 2000 Anti-HBs,
and a commercially available enzyme immunoassay for anti-HBs (Kit A),
and the results are listed in the package insert.

In the European study, six specimens from *H. pylori* positive patients,
four from antinuclear antibody (ANA) positive patients, and 27 from
patients with positive rheumatoid factor (RF) were tested by IMMULITE
Anti-HBs. IMMULITE Anti-HBs test results were negative for all six *H.
pylori* specimens, negative for 3/4 ANA specimens, and negative for
24/27 RF specimens.

In the European study, six specimens from *H. pylori* positive patients,
three from antinuclear antibody (ANA) positive patients, and 26 from
patients with positive rheumatoid factor (RF) were tested by IMMULITE
2000 Anti-HBs. IMMULITE 2000 Anti-HBs test results were negative for all
six *H. pylori* specimens and all three ANA specimens.

IMMULITE 2000 Anti-HBs results were negative for 23/26 and positive for
3/26 RF specimens.

**Effects of Bilirubin, Lipemia and Hemolysis**

To simulate moderate and severe icterus, different volumes of each of 5
patient samples ranging from negative to high positive total antibodies
against hepatitis B surface antigen were pipetted into lyophilized
unconjugated bilirubin to achieve 3 levels of bilirubin concentrations
(10, 20 and 40 mg/dL) for each sample. The spiked and unspiked samples
were assayed by the IMMULITE and IMMULITE 2000 Anti-HBs assays. In the
IMMULITE Anti-HBs tests, the spiked samples had averages of 98%, 90% and
85% recovery for all samples for 10, 20 and 40 mg/dL bilirubin
concentrations, respectively. In the IMMULITE 2000 Anti-HBs tests, the
spiked samples had averages of 96%, 97% and 95% recovery for all samples
for 10, 20 and 40 mg/dL bilirubin concentrations, respectively. This
study demonstrated that the measurement of antibodies against hepatitis
B surface antigen was not affected by the presence of bilirubin up to 40
mg/dL.

To simulate mild, moderate and severe hemolysis, the same five samples
were spiked with hemolysate to achieve final hemoglobin levels of 168,
252 and 504 mg/dL. The samples were assayed, both spiked and unspiked,
by the IMMULITE and IMMULITE 2000 Anti-HBs assays. In both the IMMULITE
and IMMULITE 2000 Anti-HBs tests, the low samples had significant
increases in the antibodies against hepatitis B surface antigen when
spiked with hemolysate. It was concluded that the measurement of
antibodies against hepatitis B surface antigen may be affected by the
presence of red blood cells. The results of hemolyzed samples should be
interpreted with caution.

The same 6 samples were each spiked with 4 levels of triglycerides at
500, 1000, 2000 and 3000 mg/dL to evaluate the effect of lipemia on the
IMMULITE and IMMULITE 2000 Anti-HBs assays. Unspiked and spiked samples
were tested by the IMMULITE and IMMULITE 2000 Anti-HBs assays. Since no
significant increases of antibody levels were observed in the spiked
samples with the increase of triglyceride levels, it was concluded that
the measurement of antibodies to hepatitis surface antigen was not
affected by the presence of lipemia (triglycerides up to 3000 mg/dL).

**Hook Effect and Carryover**

The hook effect study demonstrated that the IMMULITE and IMMULITE 2000
Anti-HBs assays did not have a hook effect up to at least 10,000 mIU/mL.

The carryover study demonstrated that the IMMULITE and IMMULITE 2000
Anti-HBs assays did not exhibit a carryover phenomenon when samples were
preceded by a sample with a very high titer of antibodies against
hepatitis B surface antigen.

**Interfering Substances**

A study was conducted to evaluate the effects of interfering substances
on IMMULITE and IMMULITE 2000 Anti-HBs assays. Potential interfering
substances that included common serum constituents, chemotherapeutic and
other drugs were spiked into serum samples with 5 or 6 different levels
of anti-HBs. Listed below are the substances and their test levels
(concentration).

![](media/image1.wmf){width="2.6631944444444446in"
height="2.6131944444444444in"}

This study demonstrated that the measurement of antibodies against
hepatitis B surface antigen by IMMULITE and IMMULITE 2000 Anti-HBs was
not affected by the presence of any of the interfering substances listed
up to the levels tested.

**Effects of Anticoagulants**

The measurement of specimens is not affected by the presence of heparin
and EDTA anti-coagulants, as shown in a study that included 46 specimens
collected into plain, heparinized and EDTA vacutainer tubes. By
regression:

> [IMMULITE Anti-HBs]{.underline}
>
> (Heparin) = 1.04 (Serum) + 10 mIU/mL r = 0.97
>
> (EDTA) = 1.11 (Serum) -- 2 mIU/mL r = 0.93
>
> Around the cutoff (10 mIU/mL), heparinized specimens demonstrated a
> 112% recovery and EDTA specimens demonstrated a 103% recovery. This
> may indicate that with heparin and EDTA, there could be false
> positives around the cut-off.
>
> [IMMULITE 2000 Anti-HBs]{.underline}
>
> (Heparin) = 1.03 (Serum) + 14 mIU/mL r = 0.97
>
> (EDTA) = 1.05 (Serum) + 16 mIU/mL r = 0.88
>
> Around the cutoff (10 mIU/mL), heparinized specimens demonstrated a
> 117% recovery and EDTA specimens demonstrated a 106% recovery. This
> may indicate that with heparin and EDTA, there could be false
> positives around the cut-off.

**Precision**

Precision studies for the IMMULITE and IMMULITE 2000 Anti-HBs assays
were conducted at three sites. Included in the studies were three
controls and nine patient samples covering the entire working range (3
-- 2000 mIU/mL) of both assays. All controls and serum samples were
assayed in duplicate over the course of 20 days, two runs per day, for a
total of 40 runs and 80 replicates at 3 US sites. The IMMULITE Anti-HBs
assay was tested for three lots and at three sites.

Results by IMMULITE and IMMULITE 2000 Anti-HBs are expressed in mIU/mL.
Statistics including the means, standard deviations, the intraassay and
total precision were calculated for samples 2 through 8. Statistics for
samples 1 and 9 were not calculated because they consistently yielded
results less than 3 mIU/mL and results greater than 2000 mIU/mL,
respectively. The IMMULITE and IMMULITE 2000 Anti-HBs lot-to-lot
precision data and the IMMULITE Anti-HBs site-to-site precision data are
also provided.

The IMMULITE 2000 Anti-HBs lot-to-lot precision has not been
evaluated*.* Because the lot-to-lot precision of the assay had
previously been established, and the Stability studies included three
lots, no additional data was required.

IMMULITE Anti-HBs Intra-assay and Total Precision (mIU/mL), IMMULITE
2000 Anti-HBs Intra-assay and Total Precision (mIU/mL), IMMULITE
Anti-HBs Lot-to-Lot and Site-to-Site Precision, and IMMULITE 2000
Anti-HBs Site-to-Site Precision data for Site 1, Site 2, and Site 3 are
included in the package insert.

EDTA and heparinized samples were assayed in duplicate in three runs on
three days at three U.S. sites for three lots of IMMULITE Anti-HBs and
one lot of IMMULITE 2000 Anti-HBs. The median total variance of
coefficients (EDTA, 4.2%; heparin, 4.5%) demonstrated that these
alternative sample types do not affect the precision of IMMULITE and
IMMULITE 2000 Anti-HBs.

**Stability**

Stability studies for IMMULITE and IMMULITE 2000 Anti-HBs were conducted
by using 3 lots of IMMULITE Anti-HBs, and one lot of IMMULITE 2000
Anti-HBs. The kits and components were subjected to different
storage/stress conditions to simulate adverse conditions that might be
encountered during shipment and use at clinical laboratories, to
establish the long-term (shelf-life) claims, to approximate and support
the real time stability and to test the robustness of individual
components.

The studies demonstrated that the performance of IMMULITE and IMMULITE
2000 Anti-HBs assays was not affected if properly stored at package
insert conditions for at least 720 days.

These studies also demonstrated that the performance of IMMULITE and
IMMULITE 2000 Anti-HBs assays was not affected following initial
stresses (37°C, or --20°C) for at least 720 days.

IX. **SUMMARY OF CLINICAL STUDIES**

**Expected Values**

Individuals acutely infected with the hepatitis B virus will exhibit
anti-HBs approximately two weeks after the disappearance of HBsAg. This
antibody response will reach peak levels after several months and
gradually decline over a period of years. The majority of persons who
have been vaccinated against HBV will also have detectable levels of
anti-HBs.

Demographics and expected prevalence rates for different categories of
subjects, (Apparently Healthy individuals, HBV Acute Patients, and HBV
Chronic Patients), each of whom provided one specimen, were obtained
from four clinical studies. The sites were: one in the northwestern
United States (Study 1), two in the southern United States (Study 3
using specimens from China and Study 4), and one in Europe, are
summarized in the package inserts. Some individuals were characterized
as at high risk or low risk of exposure to hepatitis B.

**Clinical Studies**

A total of 769 subjects were tested, using FDA-approved or licensed
hepatitis B assays (Reference markers), at four clinical sites, to
assess the performance of the IMMULITE Anti-HBs and IMMULITE 2000
Anti-HBs assays. Only initial test results are reported.

The data were analyzed following the assignment of specimen
classification based upon the reactive(+)/ nonreactive(-) patterns for
the HBV reference serological markers. Specimen classification was based
only on the HBV serological marker results for that particular specimen.
No other laboratory or clinical information was used in the disease
classification process.

**Site 1:** Conducted in the northwestern United States, this study
included 281 patients, consisting of 138 males and 88 females. Gender
for 55 subjects was not reported. These subjects had an average age of
43 years, ranging from 21 to 85 years. Distributions of the ethnicity of
the subjects are shown in the following table.

  ------------------------------------- -------------------- ------------
  Ethnicity                             *N*                  \%

  African American                      15                   5.3%

  Caucasian                             169                  60.1%

  Hispanic                              2                    0.7%

  Asian                                 32                   11.4%

  Other                                 3                    1.1%

  Unknown                               60                   21.4%

  Total                                 281                  100.0%
  ------------------------------------- -------------------- ------------

These subjects included acute and chronic hepatitis B patients,
vaccinated individuals, pregnant women, and apparently healthy
individuals, and patients with potentially crossreactive substances and
medical conditions.

A total of 281 specimens were prospectively (n=92) and retrospectively
(n=189) collected and tested by FDA-approved or licensed hepatitis B
assays for six HBV serological markers (HBsAg, Anti-HBc, Anti-HBs,
Anti-HBc IgM, HBeAg, and Anti-HBe). Characterization based on single
point specimens by the reference serological markers demonstrated 17
unique patterns:

  ----------------------------------------------------------------------------------------------
  Characterization   Number of  HBV                                                   
  based on single    patients   Reference                                             
  point specimens               Markers                                               
  ------------------ ---------- ----------- -------- ---------- ---------- ---------- ----------
                                HBsAg       HBeAg    Anti-HBc   Anti-HBc   Anti-HBe   Anti-HBs
                                                     IgM                              

                                                                                      

  Acute              2          \+          --       --         --         --         --

  Acute              1          \+          \+       --         --         --         --

  Acute              32         \+          --       +/-        \+         \+         --

  Acute              34         \+          \+       +/-        \+         --         --

  Chronic            2          \+          --       --         \+         --         --

  Chronic            3          \+          +/-      --         \+         \+         \+

  Chronic            1          \+          --       --         \+         --         \+

  Chronic            1          \+          \+       +/-        \+         --         \+

  Early Recovery     16         --          --       +/-        \+         \+         \+

  Early Recovery     4          --          --       --         \+         \+         --

  Early Recovery     19         --          --       --         \+         +/-        --

  Early Recovery     1          --          --       \+         \+         +/-        \+

  HBV vaccine        27         --          --       --         --         --         \+
  response                                                                            

  Not previously     120        --          --       --         --         --         --
  infected                                                                            

  Recovered          16         --          --       --         +/-        --         \+

  Recovered          1          --          +/-      --         \+         --         \+

  Uninterpretable    1          --          \+       --         --         --         --
  ----------------------------------------------------------------------------------------------

Based on the above classifications the IMMULITE and IMMULITE 2000
Anti-HBs results were compared to Kit A, a reference assay for the
determination of anti-HBs.

For the IMMULITE Anti-HBs the combined Total Positive agreement is 92.4%
(61/66) with a 95% CI of 83.2 to 97.5%. The Negative agreement is 97.2%
(209/215) with a 95% CI of 94.0 to 99.0%. The combined Total agreement
is 96.1% (270/281) with a 95% CI of 93.1 to 98.0%.

For the IMMULITE 2000 Anti-HBs the combined Total Positive agreement is
90.9% (60/66) with a 95% CI of 81.3 to 96.6%. The Negative agreement is
96.3% (207/215) with a 95% CI of 92.8 to 98.4%. The combined Total
agreement is 95.0% (267/281) with a 95% CI of 91.8 to 97.3%.

**Site 2:** Conducted in the northeastern United States, this study
included 209 patients, consisting of 104 males and 103 females. Gender
for two patients was not reported. These patients had an average age of
47 years, ranging from newborn to 93 years. Distributions of the
ethnicity of the patients are shown in the following table.

  ----------------------------------- -------------------- --------------
  Ethnicity                           *N*                  \%

  African American                    21                   10.0%

  Caucasian                           101                  48.3%

  Hispanic                            3                    1.4%

  Asian                               6                    2.9%

  Other                               7                    3.3%

  Unknown                             71                   34.0%

  Total                               209                  100.0%
  ----------------------------------- -------------------- --------------

Included were patients with potentially crossreactive substances and
medical conditions. A total of 209 retrospective specimens were
collected and tested by FDA-approved or licensed hepatitis B assays for
four HBV serological markers (HBsAg, Anti-HBc IgM, Anti-HBc, and
Anti-HBs). Characterization based on single point specimens by the
reference serological markers demonstrated eight unique patterns:

  ---------------------------------------------------------------------------------
  Characterization   No. of     HBV                                    
  based on single    patients   Reference                              
  point specimens               Markers                                
  ------------------ ---------- ------------ ------------ ------------ ------------
                                HBsAg        Anti-HBc IgM Anti-HBc     Anti-HBs

                                                                       

  Acute              8          \+           --           --           --

  Acute              9          \+           +/-          \+           --

  Chronic            2          \+           --           \+           \+

  Early recovery     33         --           +/-          \+           \+

  Early recovery     17         --           --           \+           --

  HBV vaccine        32         --           --           --           \+
  response                                                             

  Not previously     107        --           --           --           --
  infected                                                             

  Uninterpretable    1          \+           --           --           \+
  ---------------------------------------------------------------------------------

Based on the above classifications the IMMULITE and IMMULITE 2000
Anti-HBs results were compared to Kit A.

For the IMMULITE Anti-HBs the combined Total Positive agreement is 94.1%
(64/68) with a 95% CI of 85.6 to 98.4%. The Negative agreement is 95.0%
(134/141) with a 95% CI of 90.0 to 98.0%. The combined Total agreement
is 94.7% (198/209) with a 95% CI of 90.8 to 97.3%.

For the IMMULITE 2000 Anti-HBs the combined Total Positive agreement is
94.1% (64/68) with a 95% CI of 85.6 to 98.4%. The Negative agreement is
97.2% (137/141) with a 95% CI of 92.9 to 99.2%. The combined Total
agreement is 96.2% (201/209) with a 95% CI = 92.6 to 98.3%.

**Site 3:** Specimens obtained from China were tested in the southern
United States, this study included 79 patients and was comprised of 13
females and 55 males (gender for 11 patients was not reported) with an
average age of 36 years, ranging from 18 to 82 years. These were
prospectively recruited patients from a clinically well-characterized,
homogeneous population: acute hepatitis B patients who presented with
symptoms typical of acute hepatitis B such as jaundice, persistent
fatigue, loss of appetite, pale stools and liver enlargement. Their ALT
and AST results were significantly elevated at the time of diagnosis.

A total of 79 specimens were prospectively collected and tested by
FDA-approved or licensed hepatitis B assays for six HBV serological
markers (HBsAg, HBeAg, Anti-HBc IgM, Anti-HBc, Anti-HBeAg, and
Anti-HBs). Characterization based on single point specimens by the
reference serological markers demonstrated 11 unique patterns:

  ----------------------------------------------------------------------------------------------
  Characterization   Number of  HBV                                                   
  based on single    patients   Reference                                             
  point specimens               Markers                                               
  ------------------ ---------- ----------- -------- ---------- ---------- ---------- ----------
                                HBsAg       HBeAg    Anti-HBc   Anti-HBc   Anti-HBe   Anti-HBs
                                                     IgM                              

                                                                                      

  Acute              23         \+          --       +/-        \+         \+         --

  Acute              8          \+          +/-      \+         \+         \+         --

  Acute              1          \+          --       \+         +/-        --         --

  Acute              35         \+          \+       +/-        \+         --         --

  Acute              4          \+          \+       \+         \+         --         +/-

  Chronic            1          \+          --       --         \+         --         --

  Chronic            3          \+          +/-      --         \+         \+         --

  Chronic            1          \+          \+       +/-        \+         --         \+

  Chronic            1          \+          \+       \+         \+         \+         \+

  Recovered          1          --          --       --         +/-        --         \+

  Uninterpretable    1          \+          --       \+         \+         \+         \+
  ----------------------------------------------------------------------------------------------

Based on the above classifications the IMMULITE and IMMULITE 2000
Anti-HBs results were compared to Kit A.

For the IMMULITE Anti-HBs the combined Total Positive agreement is 25.0%
(2/8) with a 95% CI of 3.2 to 65.1%. The Negative agreement is 98.6%
(70/71) with a 95% CI of 92.4 to 100.0%. The combined Total agreement is
91.1% (72/79) with a 95% CI of 82.6 to 96.4%.

For the IMMULITE 2000 Anti-HBs the combined Total Positive agreement is
12.5% (1/8) with a 95% CI of 0.0 to 52.7%. The Negative agreement is
98.6% (70/71) with a 95% CI of 92.4 to 100.0%. The combined Total
agreement is 89.9% (71/79) with a 95% CI of 81.0 to 95.5%.

**Site 4:** Conducted in the southern United States, this study included
retrospectively collected specimens from 200 pregnant subjects. These
subjects had an average age of 28 years, ranging from 17 to 41 years.

A total of 200 specimens were tested by FDA-approved or licensed
hepatitis B assays for four HBV serological markers (HBsAg, Anti-HBc
IgM, Anti-HBc, and Anti-HBs). Characterization based on single point
specimens by the reference serological markers demonstrated three unique
patterns:

  -----------------------------------------------------------------------------
                     Number of  HBV                                 
                     subjects   Reference                           
                                Markers                             
  ------------------ ---------- ----------- ----------- ----------- -----------
  Characterization              HBsAg       Anti-HBc    Anti-HBc    Anti-HBs
  based on single                           IgM                     
  point specimens                                                   

  Early recovery     4          --          +/-         \+          \+

  Early recovery     2          --          --          \+          --

  HBV vaccine        42         --          --          --          \+
  response                                                          

  Not previously     152\*      --          --          --          --
  infected                                                          
  -----------------------------------------------------------------------------

Based on the above classifications the IMMULITE and IMMULITE 2000
Anti-HBs results were compared to Kit A. (Note: One specimen was not
tested for IMMULITE Anti-HBs or for the IMMULITE 2000 Anti-HBs.)

For the IMMULITE Anti-HBs the combined Total Positive agreement is
100.0% (46/46) with a 95% CI of 92.3 to 100.0%. The Negative agreement
is 98.7% (151/153) with a 95% CI of 95.4 to 99.8%. The combined Total
agreement is 99.0% (197/199) with a 95% CI of 96.4 to 99.9%.

For the IMMULITE 2000 Anti-HBs the combined Total Positive agreement is
100% (46/46) with a 95% CI of 92.3 to 100%. The Negative agreement is
98.7% (151/153) 95% CI of 95.4 to 99.8%. The combined Total agreement is
99.0% (197/199) 95% CI of 96.4 to 99.9%.

X.  **CONCLUSIONS DRAWN FROM STUDIES**

The studies conducted demonstrated that when used according to the
instructions for use, the IMMULITE Anti-HBs and the IMMULITE 2000
Anti-HBs has:

-   Comparable performance when testing specimens collected in serum and
    plasma (heparin or EDTA).

-   Stability for 720 days without loss of activity when stored under
    recommended conditions.

-   Precision at estimates of \<7% intra-assay, \<21% site-to-site and
    \<13% lot-to-lot.

-   Minimal cross-reactivity with antibodies to various infections
    agents when compared to the reference assay.

-   The ability to measure antibodies against hepatitis surface antigen
    in human serum or plasma. The results indicated a clinical
    sensitivity and specificity that correlate well to a commercially
    available reference assay.

**Safety**

As a diagnostic test, the anti-HBsAg assay involves 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 removed.

**Benefit/Risk Analysis**

The PMA studies provide reasonable assurance that support that 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.

-   Along with other HBV serological markers for the laboratory
    diagnosis of HBV disease associated with HBV infection.

-   To allow a differential diagnosis in individuals displaying signs
    and symptoms of hepatitis when etiology is unknown.

-   As an indication of seroconversion from hepatitis B virus (HBV)
    infection.

    The potential risks seen for these *in vitro* diagnostic tests are
    not unusual in the laboratory setting, and appropriate warnings for
    these risks are contained in the labeling and package insert
    instructions for these devices. Standard good laboratory practices
    are considered sufficient to minimize the risks to the end user.

    The benefits to HBV-infected individuals tested by these devices
    outweigh any potential adverse event or risk to the patient or user
    due to device malfunction or operator error.

XI. **PANEL RECOMMENDATIONS**

Pursuant to Section 515(c)(2) of the act as amended by the Safe Medical
Devices Act of 1990, this PMA was not the subject of an FDA Microbiology
Devices Advisory Panel meeting because the information in the PMA
substantially duplicated information previously reviewed by this Panel.

XII. **CDRH DECISION**

FDA issued an approval order on July 22, 2002.

The applicant's manufacturing facility was found to be in compliance
with the Quality Systems Regulation (21 CFR 820).

XIII. **APPROVAL SPECIFICATIONS**

Directions for Use: See labeling

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

Postapproval Requirements and Restrictions: See approval order.