**Summary of Safety and Effectiveness Data**

I.  **GENERAL INFORMATION**

Device Generic Name: Reagent system for the measurement of

antibodies against hepatitis B core

antigen

Device Trade Name: IMMULITE^^ Anti-HBc

> IMMULITE^^ 2000 Anti-HBc

Applicant's Name and Address: Diagnostic Products Corporation

> 5700 West 96^th^ Street

Los Angeles, California 90045-5597

Premarket Approval Application (PMA) Number: P010051

Date of Panel Recommendation: None

Date of Notice of Approval to the Applicant: July 24, 2002

II. **INDICATIONS FOR USE**

**IMMULITE Anti-HBc**

The IMMULITE Anti-HBc is a solid-phase chemiluminescent enzyme
immunoassay designed for use on the IMMULITE automated immunoassay
analyzer for the qualitative detection of total antibodies against
hepatitis B core antigen (anti-HBc) in human serum or plasma (EDTA,
heparinized, citrate). It is intended for *in vitro* diagnostic use for
the presumptive laboratory diagnosis of ongoing or previous hepatitis B
virus infection.

**IMMULITE 2000 Anti-HBc**

The IMMULITE 2000 Anti-HBc is a solid-phase chemiluminescent enzyme
immunoassay designed for use on the IMMULITE 2000 automated immunoassay
analyzer for the qualitative detection of total antibodies against
hepatitis B core antigen (anti-HBc) in human serum or plasma (EDTA,
heparinized, citrate). It is intended for *in vitro* diagnostic use for
the laboratory diagnosis of ongoing or previous hepatitis B virus
infection.

III. **DEVICE DESCRIPTION**

The IMMULITE and IMMULITE 2000 Anti-HBc kits are the subject of this
PMA. Data for each assay is presented separately in this document.

The IMMULITE and IMMULITE 2000 Anti-HBc 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
total antibodies against hepatitis B core antigen (HBcAg) in human serum
or plasma. The kits are intended for *in vitro* use as an aid in the
determination of a prior immune status to the hepatitis B virus.

The kits' solid phase is a polystyrene bead coated with purified
recombinant HBcAg. 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, anti-HBc in the patient sample binds to the recombinant
HBcAg-coated bead. Unbound serum is then removed by a centrifugal wash.
An alkaline phosphatase-labeled monoclonal anti-HBc antibody is
introduced, and the reaction tube is incubated with agitation for
another 30 minute cycle, during which time the monoclonal antibody binds
to unoccupied sites on the recombinant HBcAg-coated bead. 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 inversely related to the presence of
antibodies to HBcAg in the sample. A qualitative result is then obtained
by comparing the patient results to an established cutoff

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

[]{.mark}

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

> []{.mark}

Warning and precautions for users of the IMMULITE Anti-HBc and

IMMULITE 2000 Anti-HBc assays are stated in the product labeling.

V.  **ALTERNATIVE PRACTICES OR PROCEDURES**

Commercially available, FDA licensed or approved serological tests have
been used to measure antibodies against hepatitis B core antigen in
individuals suspected of having hepatitis. When patient test results are
used in combination with other serological markers expressed during the
three phases of incubation, the presence of HBV virus can be determined.

VI. **MARKETING HISTORY**

IMMULITE Anti-HBc and IMMULITE 2000 Anti-HBc 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-HBc 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-HBc 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.

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-HBc, IMMULITE 2000 Anti-HBc,
and a commercially available enzyme immunoassay for anti-HBc (Kit A),
and the results are listed in the package insert.

In the European study, eight specimens from antinuclear antibody (ANA)
positive patients and 28 specimens from patients with positive
rheumatoid factor (RF) were tested by IMMULITE Anti-HBc. IMMULITE
Anti-HBc test results were all negative for the eight ANA specimens.
IMMULITE Anti-HBc test results were negative for 25/28 RF specimens and
positive for 3/28 RF specimens.

The specimens were also tested by IMMULITE 2000 Anti-HBc, and the
results are listed in the package insert.

In the European study, eight specimens from antinuclear antibody (ANA)
positive patients were tested by IMMULITE 2000 Anti-HBc. IMMULITE 2000
Anti-HBc test results were negative for all eight ANA specimens.

**Analytical Sensitivity**

Based on studies with serial dilution of Paul Erlich Institute reference
material Anti-HBc IgG 100 U/mL, the analytical sensitivity (last
positive dilution) for IMMULITE 2000 Anti-HBc is 0.42 PEI U/mL. The 95%
confidence interval at this level (0.42 PEI IU/mL) is 0.37 - 0.48 PEI
U/mL precision of IMMULITE and IMMULITE 2000 Anti-HBc.

**Precision**

Precision studies for the IMMULITE and IMMULITE 2000 Anti-HBc assays
were conducted at three sites. Three controls and six patient samples
with different hepatitis B core antibody levels representing negative,
high negative, around the cutoff, low positive, medium positive and high
positive samples were evaluated. All controls and samples were tested in
duplicate by three different IMMULITE Anti-HBc kit lots and one IMMULITE
2000 Anti-HBc kit lot for a total of 40 runs at each of the three sites.

Statistics including the means, standard deviations, intra-assay and
total precision were based on the adjustor to sample CPS ratios in the
summary shown below.

EDTA, heparin and sodium citrate samples were assayed in duplicate in
three runs on three days at three U.S. sites for three lots of IMMULITE
Anti-HBc and one lot of IMMULITE 2000 Anti-HBc. The median total
variance of coefficients (EDTA, 4.9%; heparin, 4.4%; sodium citrate,
5.5%) demonstrated that these alternative sample types do not affect the
precision of IMMULITE and IMMULITE 2000 Anti-HBc.

The IMMULITE 2000 Anti-HBc 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.

**Effects of Anticoagulants**

The measurement of specimens is not significantly affected by the
presence of heparin. IMMULITE 2000 Anti-HBc results were negative for
23/26 and positive for 3/26 RF specimens. EDTA, heparin, and sodium
citrate samples were assayed in duplicate in three runs on three days at
three U.S. sites for three lots of IMMULITE Anti-HBc and one lot of
IMMULITE 2000 Anti-HBc. The median total variance of coefficients (EDTA,
4.9%; heparin, 4.4%; sodium citrate, 5.5%) demonstrated that these
alternative sample types do not affect the sodium citrate, or EDTA
anti-coagulants, as shown in a study (Study 1) that included 57
specimens collected into plain, heparinized, sodium citrate, and EDTA
vacutainer tubes. Data graphs are in the package insert. The following
is a summary showing cutoff-to-signal rations with correlation
regression (r =).

> IMMULITE Anti-HBc (in cutoff-to-signal ratio)

(Heparin) = 1.08 (Serum) + 0.006 r = 0.99

(Na Citrate) = 1.10 (Serum) + 0.026 r = 0.95

(EDTA) = 0.99 (Serum) + 0.034 r = 0.98

> In another study, 18 specimens collected into plain and sodium citrate
> vacutainer tubes were tested by IMMULITE Anti-HBc assay. By
> regression: (in cutoff-to-signal ratio)

(Na Citrate) = 1.14 (Serum) -- 1.54. r = 0.97

> IMMULITE 2000 Anti-HBc (in cutoff-to-signal ratio)

(Heparin) = 0.98 (Serum) + 0.018 r = 0.99

(Na Citrate) = 1.07 (Serum) + 0.027 r = 0.94

(EDTA) = 0.97 (Serum) + 0.031 r = 0.99

> In another study, 18 specimens collected into plain and sodium citrate
> vacutainer tubes were tested by IMMULITE 2000 Anti-HBc assay. By
> regression: (in cutoff-to-signal ratio)

(Na Citrate) = 0.92 (Serum) + 0.776 r = 0.91

**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 2000 Anti-HBc and a commercially
available enzyme immunoassay for anti-HBc (Kit A). The data is presented
in the package insert.

In the European study, eight specimens from antinuclear antibody (ANA)
positive patients were tested by IMMULITE 2000 Anti-HBc. IMMULITE 2000
Anti-HBc test results were negative for all eight ANA specimens.

**Effects of Bilirubin, Lipemia and Hemolysis**

To simulate moderate and severe icterus, different volumes of each of 5
patient samples ranging from very 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, and 20 mg/dL) for each sample. The spiked and
unspiked samples were assayed by the IMMULITE and IMMULITE 2000 Anti-HBc
assays. In the IMMULITE Anti-HBc tests, the spiked samples had averages
of 98%, and 90% recovery for all samples for 10, and 20 mg/dL bilirubin
concentrations, respectively. In the IMMULITE 2000 Anti-HBc tests, the
spiked samples had averages of 96%, and 97% recovery for all samples for
10, and 20 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 20
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-HBc assays. In both the IMMULITE
and IMMULITE 2000 Anti-HBc 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 lipemia effect on the
IMMULITE and IMMULITE 2000 Anti-HBc assays. Unspiked and spiked samples
were tested by the IMMULITE and IMMULITE 2000 Anti-HBc 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-HBc 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-HBc 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-HBc 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-HBc. 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-HBc was
not affected by the presence of any of the interfering substances listed
up to the levels tested.

**Stability**

Stability studies for IMMULITE and IMMULITE 2000 Anti-HBc were conducted
by using 3 lots of IMMULITE Anti-HBc, and one lot of IMMULITE 2000
Anti-HBc. 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-HBc 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-HBc 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-HBc 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-HBc.

Demographics and expected prevalence rates for different categories of
subjects (apparently healthy individuals, HBV Chronic Patients, HBV
Acute Patients and individuals at high risk or low risk of exposure to
hepatitis B.) each of whom provided one specimen, from four clinical
studies, 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 insert.

**Clinical Studies**

The sponsor conducted clinical studies at four sites to assess the
performance of the IMMULITE Anti-HBc assay and IMMULITE 2000 Anti-HBc.
The study included 908 subjects, whose status was determined using
FDA-approved or licensed hepatitis B assays (Reference markers), of
those 139 specimens were evaluated in a comparison study. Only initial
test results were reported in the analyses.

The data were analyzed using the test results obtained from the HBV
reference serological marker assays, reactive(+)/ nonreactive(-).
Specimen designation was based only on the HBV serological marker
results for that particular specimen. No other laboratory or clinical
information was used in the characterization 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 cross-reactive 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:

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

                                                                                      

  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 Anti-HBc and IMMULITE
2000 Anti-HBc results were compared to Kit A, a reference assay for the
determination of anti-HBc. Data charts are presented in the package
insert.

For the IMMULITE Anti-HBc the combined Total Positive agreement is 87.7%
(114/130) with a 95% CI of 80.8 to 92.8%. The Negative agreement is
98.7% (149/151) with a 95% CI of 95.3 to 99.8%. The combined Total
agreement is 93.6% (263/281) with a 95% CI of 90.1 to 96.2%.

For the IMMULITE 2000 Anti-HBc the combined Total Positive agreement is
88.7% (114/130) with a 95% CI of 80.8 to 92.8%. The Negative agreement
is 99.3% (150/151) with a 95% CI of 96.4 to 100.0%. The Total agreement
is 94.0% (264/281) with a 95% CI of 90.5 to 96.4%.

**Site 2:** Conducted in the northeastern United States, this study
included 209 patients, consisting of 104 males, 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 cross-reactive 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:

+--------------+-----------+--------+----------+----------+----------+
|              | > No. of  | HBV    |          |          |          |
|              | >         | Ref    |          |          |          |
|              |  patients | erence |          |          |          |
|              |           | M      |          |          |          |
|              |           | arkers |          |          |          |
+==============+===========+========+==========+==========+==========+
| Char         |           | HbsAg  | Anti-HBc | Anti-HBc | Anti-HBs |
| acterization |           |        | IgM      |          |          |
| based on     |           |        |          |          |          |
| single point |           |        |          |          |          |
| specimens    |           |        |          |          |          |
+--------------+-----------+--------+----------+----------+----------+
|              |           |        |          |          |          |
+--------------+-----------+--------+----------+----------+----------+
| Acute        | 8         | \+     | --       | --       | --       |
+--------------+-----------+--------+----------+----------+----------+
| Acute        | 9         | \+     | +/-      | \+       | --       |
+--------------+-----------+--------+----------+----------+----------+
| Chronic      | 2         | \+     | --       | \+       | \+       |
+--------------+-----------+--------+----------+----------+----------+
| Early        | 33        | --     | +/-      | \+       | \+       |
| recovery     |           |        |          |          |          |
+--------------+-----------+--------+----------+----------+----------+
| Early        | 17        | --     | --       | \+       | --       |
| recovery     |           |        |          |          |          |
+--------------+-----------+--------+----------+----------+----------+
| HBV vaccine  | 32        | --     | --       | --       | \+       |
| response     |           |        |          |          |          |
+--------------+-----------+--------+----------+----------+----------+
| Not          | 107       | --     | --       | --       | --       |
| previously   |           |        |          |          |          |
| infected     |           |        |          |          |          |
+--------------+-----------+--------+----------+----------+----------+
| Uni          | 1         | \+     | --       | --       | \+       |
| nterpretable |           |        |          |          |          |
+--------------+-----------+--------+----------+----------+----------+

Based on the above classifications the IMMULITE Anti-HBc and IMMULITE
2000 Anti-HBc results were compared to Kit A. Data charts are presented
in the package insert.

For the IMMULITE Anti-HBs the combined Total Positive agreement is 91.8%
(56/61) with a 95% CI of 81.9 to 97.3%. The Negative agreement is 99.3%
(147/148) with a 95% CI of 96.3 to 100.0%. The combined Total agreement
is 97.1% (203/209) with a 95% CI of 93.9 to 98.9%.

For the IMMULITE 2000 Anti-HBs the combined Total Positive agreement is
91.8% (56/61) with a 95% CI of 81.9 to 97.3%. The Negative agreement is
99.3% (147/148) with a 95% CI of 96.3 to 100.0%. The combined Total
agreement is 97.1% (203/209) with a 95% CI of 93.9 to 98.9%

**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 using
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:

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

                                                                                      

  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 Anti-HBc and IMMULITE
2000 Anti-HBc results were compared to Kit A. The data charts are
presented in the package insert.

For the IMMULITE Anti-HBs the combined Total Positive agreement is
100.0% (79/79) with a 95% CI of 95.4 to 100.0%. There were no negative
specimens therefore the Negative agreement could not be calculated.

For the IMMULITE 2000 Anti-HBs the combined Total Positive agreement is
100.0% (79/79) with a 95% CI = 95.4 to 100.0%. There were no negative
specimens therefore the Negative agreement could not be calculated

**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 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                                                        
  --------------------------------------------------------------------------

> \*Two specimens were not tested for IMMULITE Anti HBc.

Based on the above classifications the IMMULITE Anti-HBc and IMMULITE
2000 Anti-HBc results were compared to Kit A. The data charts are
presented in the package insert.

For the IMMULITE Anti-HBs the combined Total Positive agreement is 66.7%
(4/6) with a 95% CI of 22.3 to 95.7%. The Negative agreement is 99.5%
(191/192) with a 95% CI of 97.1 to 100.0%. The combined Total agreement
is 98.5% (195/198) with a 95% CI of 95.6 to 99.7%.

For the IMMULITE 2000 Anti-HBs the combined Total Positive agreement is
66.7% (4/6) with a 95% CI of 22.3 to 95.7%. The Negative agreement is
100.0% (194/194) with a 95% CI of 98.1 to 100.0%. The combined Total
agreement is 99.0% (198/200) with a 95% CI of 96.4 to 99.9%.

**Site 5:** In an additional study conducted at Diagnostic Products
Corporation, IMMULITE Anti-HBc was compared to IMMULITE 2000 Anti-HBc.
Presented below are the comparisons between IMMULITE and IMMULITE 2000
Anti-HBc on a total of 139 specimens.

  ---------- ------ ------ ------- ------- ------ ------ ----- ----- ----------
  IML                                                                Total
  Anti-HBc                                                           

  \+                       Ind                    --                 

  IML 2000                                                           
  Anti-HBc                                                           

  \+         Ind    --     \+      Ind     --     \+     Ind   --    

  78         0      1      0       0       0      0      0     60    139
  ---------- ------ ------ ------- ------- ------ ------ ----- ----- ----------

Positive agreement = 100.0% (78/78)

95% CI = 95.4 to 100.0%

Negative agreement = 98.4% (60/61)

95% CI = 91.2 to 100.0%

Total agreement = 99.3% (138/139)

95% CI = 96.1 to 100.0%

X.  **CONCLUSIONS DRAWN FROM STUDIES**

The data from both the non-clinical and clinical studies demonstrate
acceptable performance is obtained with the IMMULITE and IMMULITE 2000
Anti-HBc assays when used as directed in the package insert.

**Safety**

As a diagnostic test, the anti-HBcAg 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. The misdiagnosis due to false negative or false
positive results, or inappropriate use of the assay, can affect the safe
use of the assay.

**Benefit/Risk Analysis**

The PMA studies provide reasonable assurance that the IMMULITE and
IMMULITE 2000 Anti-HBs 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 RECOMMENDATION**

> 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**

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

FDA issued an approval order on July 24, 2002.

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.