**Draft Guidance for Industry and FDA Staff**

**Class II Special Controls Guidance Document: Hepatitis A Serological
Assays for the Clinical Laboratory Diagnosis of Hepatitis A Virus**

***Draft Guidance***

**This guidance document is being distributed for comment purposes
only.**

**Document issued on: [\[release date of FR Notice\]]{.mark}**

Comments and suggestions regarding this draft document should be
submitted within 90 days of publication in the *Federal Register* of the
notice announcing the availability of the draft guidance. Submit written
comments to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Alternatively, electronic comments may be submitted to
<http://www.fda.gov/dockets/ecomments>. All comments should be
identified with the docket number 2004D-0385.

For questions regarding this document contact Sally Hojvat Ph.D.,
Division of Microbiology Devices at 301-594-2096 or by email:
<syh@cdrh.fda.gov>.

![](media/image1.png)

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Devices and Radiological Health**

**Division of Microbiology Devices**

**Office of *In Vitro* Diagnostic Evaluation and Safety**

**Preface**

**Additional Copies**

Additional copies are available from the Internet at:
<http://www.fda.gov/cdrh/oivd/guidance/1536.pdf>, or to receive this
document via your fax machine, call the CDRH Facts-On-Demand system at
800-899-0381 or 301-827-0111 from a touch-tone telephone. Press 1 to
enter the system. At the second voice prompt, press 1 to order a
document. Enter the document number (1536) followed by the pound sign
(#). Follow the remaining voice prompts to complete your request.

> **Table of Contents**

[1. Introduction 4](#introduction)

[2. Background 5](#background)

[3. The Content and Format of an Abbreviated 510(k) Submission
6](#the-content-and-format-of-an-abbreviated-510k-submission)

[4. Scope 8](#scope)

[5. Risks to Health 8](#risks-to-health)

[6. Device Description 10](#device-description)

[7. Performance Characteristics 10](#performance-characteristics)

[8. Prevalence (Expected Values) 13](#prevalence-expected-values)

[9. Methods Comparison 13](#methods-comparison)

[10. Labeling 14](#labeling)

**Draft Guidance for Industry and FDA Staff**

**Class II Special Controls Guidance Document:**

**Hepatitis A Serological Assays for the Clinical**

**Laboratory Diagnosis of Hepatitis A Virus**

***This draft guidance, when finalized, will represent the Food and Drug
Administration\'s (FDA\'s) current thinking on this topic. It does not
create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach, contact the
FDA staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number listed
on the title page of this guidance.***

# Introduction

This draft guidance document was developed as a special controls
guidance document to support the reclassification of hepatitis A virus
serological assays \[immunoglobulin M (IgM) antibody, immunoglobulin G
(IgG) antibody, and total antibodies (IgM and IgG)\] into class II.
Hepatitis A virus (HAV) serological assays are devices that consist of
antigens and antisera for the detection of HAV-specific IgM, IgG, or
total antibodies (IgM and IgG), in human serum or plasma. These devices
are used for testing specimens from individuals who have signs and
symptoms consistent with acute hepatitis or for determining if an
individual has been previously infected with HAV. The detection of these
antibodies aids in the clinical laboratory diagnosis of an acute or past
infection by HAV in conjunction with other clinical laboratory findings.
These devices are not intended for screening blood or solid or soft
tissue donors.

This draft guidance is issued in conjunction with a *Federal Register*
notice announcing the proposal to reclassify HAV serological assays
\[IgM antibody, IgG antibody and total antibodies (IgM and IgG)\] from
class III to class II and to codify the classification at 21 CFR
866.3310.[^1] This guidance document is issued for comment purposes
only. If a final rule to reclassify this device type is not issued, this
guidance document will not be issued as a special control.

Following the effective date of a final rule reclassifying these
devices, any firm submitting a premarket notification (510(k)) for an
HAV serological assay will need to address the risks covered in the
special controls guidance document. However, the firm need only show
that its device meets the recommendations of the guidance or in some
other way provides equivalent assurances of safety and effectiveness.

FDA's guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency's current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

**The Least Burdensome Approach**

> This draft guidance document reflects our careful review of what we
> believe are the relevant issues related to HAV serological assays and
> what we believe would be the least burdensome way of addressing these
> issues. If you have comments on whether there is a less burdensome
> approach, however, please submit your comments as indicated on the
> cover of this document.

# Background

FDA believes that special controls, when combined with the general
controls, will be sufficient to provide reasonable assurance of the
safety and effectiveness of HAV serological assays. A manufacturer who
intends to market a device of this generic type should (1) conform to
the general controls of the Federal Food, Drug, and Cosmetic Act (the
Act), including the premarket notification requirements described in [21
CFR part
807](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=807&showFR=1),
subpart E, (2) address the specific risks to health associated with HAV
serological assays identified in this guidance and, (3) obtain a
substantial equivalence determination from FDA prior to marketing the
device.

This guidance document identifies the classification regulation and
product code for HAV serological assays (Refer to Section 4 --
**[Scope](#__RefHeading___Toc52173678))**. In addition, other sections
of this guidance document list the risks to health identified by FDA and
describe measures that, if followed by manufacturers and combined with
the general controls, will generally address the risks associated with
these assays and lead to a timely 510(k) review and clearance. This
document supplements other FDA documents regarding the specific content
of a 510(k) submission. You should also refer to [21 CFR
807.87](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=807.87)
and CDRH\'s **Device Advice** <http://www.fda.gov/cdrh/devadvice/>.

As described in **"The New 510(k) Paradigm - Alternate Approaches to
Demonstrating Substantial Equivalence in Premarket Notifications; Final
Guidance**," <http://www.fda.gov/cdrh/ode/parad510.html>, a manufacturer
may submit a Traditional 510(k) or has the option of submitting either
an Abbreviated 510(k) or a Special 510(k). FDA believes an Abbreviated
510(k) provides the least burdensome means of demonstrating substantial
equivalence for a new device, particularly once FDA has issued a
guidance document. Manufacturers considering modifications to their own
cleared devices may lessen the regulatory burden by submitting a Special
510(k).

# The Content and Format of an Abbreviated 510(k) Submission

An Abbreviated 510(k) submission must include the required elements
identified in 21 CFR 807.87, including the proposed labeling for the
device sufficient to describe the device, its intended use, and the
directions for its use. In an Abbreviated 510(k), FDA may consider the
contents of a summary report to be appropriate supporting data within
the meaning of 21 CFR 807.87(f) or (g); therefore, we recommend that you
include a summary report. The report should describe how this guidance
document was used during the device development and testing and should
briefly describe the methods or tests used and a summary of the test
data or description of the acceptance criteria applied to address the
risks identified in this document, as well as any additional risks
specific to your device. This section suggests information to fulfill
some of the requirements of 807.87 as well as some other items that we
recommend you include in an Abbreviated 510(k).

### Coversheet {#coversheet .unnumbered}

The coversheet should prominently identify the submission as an
Abbreviated 510(k) and cite the title of this guidance document.

### Proposed labeling {#proposed-labeling .unnumbered}

Proposed labeling should be sufficient to describe the device, its
intended use, and the directions for its use. (Refer to Section 10 for
specific information that should be included in the labeling for devices
of the types covered by this guidance document.)

### Summary report {#summary-report .unnumbered}

We recommend that the summary report contain:

#### A description of the device and its intended use. We recommend that the description include a complete discussion of the performance specifications and, when appropriate, detailed, labeled drawings of the device. Refer to section 6 for specific information that we recommend you include in the device description for devices of the type covered by this guidance document. You should also submit an "indications for use" enclosure.[^2]

#### A description of device design requirements.

#### An identification of the Risk Analysis method(s) used to assess the risk profile in general as well as the specific device's design and the results of this analysis. (Refer to Section 5 for the risks to health generally associated with the use of this device that FDA has identified.)

#### A discussion of the device characteristics that address the risks identified in this guidance document, as well as any additional risks identified in your risk analysis. 

#### A brief description of the test method(s) you have used or intend to use to address each performance aspect identified in Sections 7-9 of this guidance document. If you follow a suggested test method, you may cite the method rather than describing it. If you modify a suggested test method, you may cite the method but should provide sufficient information to explain the nature of and reason for the modification. For each test, you may either (1) briefly present the data resulting from the test in clear and concise form, such as a table, **[or]{.underline}** (2) describe the acceptance criteria that you will apply to your test results.[^3] (See also [21 CFR 820.30](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=820.30), Subpart C - Design Controls for the Quality System Regulation.)

#### If you choose to rely on a recognized standard for any part of the device design or testing, you may include either: (1) a statement that testing will be conducted and meet specified acceptance criteria before the product is marketed; or (2) a declaration of conformity to the standard.[^4] Because a declaration of conformity is based on results from testing, we believe you cannot properly submit a declaration of conformity until you have completed the testing the standard describes. For more information, please refer to section 514(c)(1)(B) of the Act and the FDA guidance, **Use of Standards in Substantial Equivalence Determinations; Final Guidance for Industry and FDA**, [http://www.fda.gov/cdrh/ode/guidance/1131.html.]{.underline} 

If it is not clear how you have addressed the risks identified by FDA or
additional risks identified through your risk analysis, we may request
additional information about aspects of the device's performance
characteristics. We may also request additional information if we need
it to assess the adequacy of your acceptance criteria. (Under 21 CFR
807.87(l), we may request any additional information that is necessary
to reach a determination regarding substantial equivalence.)

As an alternative to submitting an Abbreviated 510(k), you can submit a
Traditional 510(k) that provides all of the information and data
required under 21 CFR 807.87 and described in this guidance. A
Traditional 510(k) should include all of your methods, data, acceptance
criteria, and conclusions. Manufacturers considering modifications to
their own cleared devices should consider submitting Special 510(k)s.

The general discussion above applies to any device subject to a special
controls guidance document. The following is a specific discussion of
how you should apply this special controls guidance document to a 510(k)
submission for HAV serological assays.

# Scope

The scope of this document is limited to Hepatitis A Virus Serological
Assays \[IgM antibody, IgG antibody, and total antibodies (IgM and
IgG)\] (product code: LOL):

In the companion proposed rule, FDA is proposing the following
identification:

Hepatitis A virus serological assays are devices that consist of
antigens and antisera for the detection of hepatitis A virus-specific
IgM, IgG, or total antibodies (IgM and IgG), in human serum or plasma.
These devices are used for testing specimens from individuals who have
signs and symptoms consistent with acute hepatitis or for determining if
an individual has been previously infected with the hepatitis A virus.
The detection of these antibodies aids in the clinical laboratory
diagnosis of an acute or past infection by hepatitis A virus in
conjunction with other clinical laboratory findings. These devices are
not intended for screening blood or solid or soft tissue donors.

# Risks to Health

There are no known *direct* risks to an individual's health associated
with the device. However, failure of HAV serological assays to perform
as indicated or an error in interpretation of results may lead to
improper patient management. There are no clinical features that
distinguish HAV infection from infection by other etiologic agents of
hepatitis such as hepatitis B virus (HBV) or hepatitis C virus (HCV).
HAV serological assays are used to aid in this distinction. Therefore,
false test results could contribute to improper patient management,
which includes misdiagnosis.

A false negative measurement with failure to detect HAV-specific IgM
would misdiagnose an active HAV infection. False negative HAV
serological assays results may place individuals infected with
preexisting liver disease at risk for not receiving appropriate therapy.
Such false negative test results may also have serious adverse public
health consequences because HAV infected individuals, e.g.,
food-handlers, may not receive appropriate counseling in regard to
prevention of communicating HAV infection to others. It has also been
shown that HAV infection in individuals with preexisting liver disease,
e.g., HCV infection, has been associated with an increased rate of
fulminant hepatitis and mortality \[References 1-3\]. The administration
of HAV-specific hyperimmune globulin may help to prevent or improve the
clinical manifestations of disease if given within two weeks of
infection as prophylaxis, although it is generally not helpful in the
acute phase of HAV infection \[Ref. 4\]. In healthy individuals, HAV
infections are generally self-limiting without serious consequences,
with no chronic or persistent hepatitis \[Ref. 5\].

In addition, the failure to detect HAV-specific total or IgG antibodies
would result in misdiagnosis of past infection and may cause individuals
to erroneously receive vaccination for HAV. This would be of minimal
risk, however, since there is no contraindication for an individual
immune to HAV receiving HAV vaccination.

A false positive measurement can result in incorrect diagnosis of active
or past HAV infection. If HAV-specific total antibodies are detected
erroneously, an individual may not receive the vaccine for HAV and could
continue to be at risk for HAV infection. A false positive anti-HAV IgM
result also has public health considerations because the majority of
state health departments are required to follow-up reported acute HAV
infections. This would place an undue burden on state health department
resources.

In the table below, FDA has identified the risk to health generally
associated with the use of assays for HAV-specific antibodies addressed
in this document. The measures recommended to mitigate this identified
risk are given in this guidance document, as shown in the table below.
We recommend that you conduct a risk analysis, prior to submitting your
premarket notification, to identify any other risks specific to your
device. The premarket notification should describe the risk analysis
method. If you elect to use an alternative approach to address the risk
identified in this document, or have identified risks additional to
those in this document, you should provide sufficient detail to support
the approach you have used to address that risk.

  ---------------------------------- ------------------------------------
  **Identified risk**                **Recommended mitigation measures**

  Improper patient management        [Sections
                                     6](#__RefHeading___Toc52173680)-10
  ---------------------------------- ------------------------------------

# Device Description

We recommend that you include the following in your device description:

-   a description of the method that your device uses to detect
    HAV-specific IgM, IgG, or total antibodies (e.g., Enzyme
    Immunoassay)

-   a description of the reagent components included with the kit

-   information on the antibodies detected or measured

-   a clear explanation for the specific controls and calibrators to be
    used in the assay

-   a description of the primary purpose for the quality control
    material.

In your description of reagent components, you should furnish the
antigen source and explain how it was characterized. If a recombinant
antigen is used, you should supply specific information concerning the
specific HAV epitopes present on the antigen and specific information
for antigen characterization. For monoclonal antibodies, you should give
specific information concerning HAV epitopes that will be detected, and
provide appropriate antibody characterization.

# Performance Characteristics 

## General Study Recommendations {#general-study-recommendations .unnumbered}

We recommend that you test specimens from individuals that have been
vaccinated against HAV. You should evaluate a baseline specimen
(prevaccination) and a post vaccination specimen collected two to four
weeks post vaccination from individuals aged two years and greater. In
your study, you should include all vaccines that are currently U.S.
licensed. If the assay's capture antigen is different than the vaccine
strain, you should explain why this will not produce a false negative
result when testing for immunity due to vaccination.

## Analytical Studies {#analytical-studies .unnumbered}

## [Specimen collection and handling conditions]{.underline} {#specimen-collection-and-handling-conditions .unnumbered}

We recommend that you substantiate statements in your labeling about
specimen storage and transport by assessing whether the device can
maintain acceptable performance (e.g., reproducibility) over the storage
times and temperatures recommended to users. For example, an appropriate
study may include an analysis of aliquots stored under the conditions of
time, temperature, or number of freeze/thaw cycles that you recommend to
users of the device. We recommend that you state the criteria for an
acceptable range of recoveries under the recommended storage and
handling conditions. \[See "Procedures for Handling and Processing of
Blood Specimens;" Approved Guideline, National Committee for Clinical
Laboratory Standards (NCCLS), Document H18-A.\]

## [Reproducibility]{.underline} {#reproducibility .unnumbered}

We recommend that you characterize intra- and inter-assay
reproducibility according to guidelines provided in the "User Protocol
for Evaluation of Qualitative Test Performance;" Approved Guideline,
NCCLS, EP12-A. This document includes guidelines for experimental
design, statistical analysis, and a format for stating performance
claims. We recommend that you use patient samples, your assay
calibrator(s), and the quality control materials that you supply or
recommend for your device for this characterization. We recommend that
you evaluate reproducibility at relevant measurements, including levels
near medical decision points and measurements near the limits of the
reportable range.

If your device is indicated for use in matrices other than serum, we
recommend that you establish the reproducibility of the assays in each
matrix, e.g., EDTA anticoagulated plasma.

We recommend that you include the following items:

#### point estimates of the concentration for levels of anti-HAV

#### standard deviations of intra- and inter-assay reproducibility 

#### sites at which the reproducibility protocol was run 

#### number of days, runs, and observations 

#### number of sites and/or operators. 

We recommend that you identify which factors (e.g., instrument
calibration, reagent lots, and operators) were held constant and which
were varied during the evaluation. Describe the computational methods,
if they are different from that described in the most current NCCLS
EP12-A, and "Evaluation of Precision Performance of Clinical Chemistry
Devices;" Approved Guideline-2^nd^ Edition, NCCLS Document EP5-A2.

If your assay requires, or you recommend, automated instrumentation, we
recommend that you perform the above-mentioned reproducibility with
three different instrument builds, i.e., different instrument serial
numbers.

### [Interference]{.underline} {#interference .unnumbered}

We recommend that you characterize the effects of potential interferents
on assay performance. Examples of experimental designs, including
guidelines for selecting interferents for testing, are described in
detail in "Interference Testing in Clinical Chemistry; Approved
Guideline," NCCLS, EP7-A. Potential sources of interference can include
compounds normally found in serum, such as triolein (triglycerides),
hemoglobin, bilirubin, and serum albumin, as well as potential
serum-based interference by rheumatoid factor (RF), anti-nuclear
antibodies (ANA), and heterophilic antibodies.

We recommend that you include the following items:

#### types and levels of interferents tested 

#### antibody level in the sample, including description of how the levels of antibodies were determined

#### number of replicates tested 

#### definition or method for computing interference. 

We recommend that you identify any observed trends in bias (i.e.,
negative or positive) and indicate the range of observed recoveries in
the presence of the particular interferent. This approach is more
informative than listing average recoveries alone. We recommend that you
state your criteria or level for determining non-interference.

You may not need to perform additional interference testing with
potential interferents of your assay that have already been identified
in literature or by other sources. However, you may address additional
potential interferents with appropriate citations in the labeling.

## [Cross-reactivity]{.underline} {#cross-reactivity .unnumbered}

We recommend that you include data on assay specificity by measuring the
cross‑reactivity of your device with antibodies to other relevant
microorganisms. In particular, studies should be performed to
characterize performance in the presence of antibodies to other viruses
that cause hepatitis \[e.g., Epstein Barr Virus (EBV), HBV, HCV,
cytomegalovirus (CMV), rubeola virus, mumps virus, and varicella zoster
virus (VZV)\], and other microorganisms that cause hepatitis (e.g.,
*Toxoplasma gondii*). If your antigen is recombinant, we recommend that
you provide cross-reactivity studies against the recombinant vector. For
HAV IgM assays, we recommend that you include performance in the
presence of such factors as rheumatoid factor, anti-nuclear antibodies,
and human anti-mouse antibodies.

## [Cut-off points]{.underline} {#cut-off-points .unnumbered}

We recommend that you furnish data to explain how your clinically
relevant cut-off point was selected and established. You should provide
information on the use of an equivocal zone for testing. If you believe
an equivocal zone is inappropriate, you should provide an explanation
for this since there is not a confirmation assay for anti-HAV.

## [Other analytical studies]{.underline} {#other-analytical-studies .unnumbered}

We recommend that you test seroconversion panels. Many of these panels
are commercially available. If a commercial panel is used, we recommend
that you reassess the reported reactivity with a legally marketed assay.

We recommend that you test against recognized standards for anti-HAV,
e.g., Paul Ehrlich-Institute or World Health Organization (National
Institute for Biological Standards and Control) standards, to determine
the assay's analytical sensitivity, i.e., limit of detection (LoD).

If a matrix other than serum is recommended, e.g., EDTA or sodium
heparin anticoagulated plasma, you should furnish information
demonstrating that there is no or minimal assay effect when these
anticoagulants are compared to serum.

# Prevalence (Expected Values)

We recommend that you establish the prevalence of HAV antibodies in a
normal population (healthy individuals without symptoms) using the
specified cut-off. You should assay a statistically significant number
of samples that are representative of the intended use, clinical
utility, and matrix of the samples. It is only necessary to furnish
results using your device. We recommend that you summarize the
distribution of the population according to age groups (in decades),
gender, geographical area, and the number of positive, negative, and
equivocal results. We recommend that blood donors not be used for this
study.

# Methods Comparison 

We recommend that you evaluate your assay at three sites, one of which
may be the manufacturer\'s site. We recommend that you assess
performance in the testing environment where the device will ultimately
be used (i.e., clinical laboratory) by individuals who will use the test
in clinical practice (e.g., trained technologists). We recommend that
you initially analyze data from each study site separately to evaluate
any inter-site variation and include results of the analysis in the
510(k) summary report. It may be possible to pool clinical study results
from the individual sites in the package insert if you can demonstrate
that there are no significant differences in the results or populations
among sites. Before initiating any clinical study, you may contact the
Division of Microbiology Devices.

So that acceptance criteria or data summaries can be best interpreted
during the review, we recommend that you provide appropriate specific
information concerning protocols. The information is also necessary to
aid users in interpreting information in your labeling. For example,
when referring to NCCLS protocols or guidelines, we recommend that you
indicate which specific aspects of the protocols or guidelines you
followed.

## Detectability and Comparative Performance {#detectability-and-comparative-performance .unnumbered}

We recommend that you determine the detectability of antibody to HAV by
comparing test performance with a legally marketed device (predicate
device) or by testing against an appropriate algorithm that will
diagnose HAV acute and past infection. Prospective collection of
specimens is recommended. However, repository banks may be used as the
source for samples if they contain well characterized specimens that
were collected from one site over a contiguous time period. This
characterization should include information supporting sample integrity,
demonstrating appropriate selection, and clinical laboratory
characterization of samples being used from a repository bank. You
should consider and address sources of bias.

## Sample Selection, Inclusion and Exclusion Criteria {#sample-selection-inclusion-and-exclusion-criteria .unnumbered}

We recommend that you evaluate samples from the intended use population
(i.e., individuals with signs and symptoms of hepatitis) in a
prospective study, and provide a clear description of how the samples
were selected, including reasons that samples were excluded.

Appropriate sample size of the indicated population depends on factors
such as reproducibility, interference, and other performance
characteristics of the test. We recommend that you provide a statistical
justification to support the sample size of the study population.

## Presentation of Results {#presentation-of-results .unnumbered}

We recommend that you furnish line data for all studies. You may supply
this information electronically using Microsoft EXCEL, delimited text
files, or SAS files.

# Labeling 

The premarket notification should include labeling in sufficient detail
to satisfy the requirements of 21 CFR 807.87(e). The following
suggestions are aimed at assisting you in submitting labeling that
satisfies the requirements of 21 CFR 807.87(e) and preparing final
labeling.[^5]

## Directions for Use {#directions-for-use .unnumbered}

You should provide clear and concise instructions that delineate the
technological features of the specific device and how the device is to
be used on patients. Instructions should encourage local/institutional
training programs designed to familiarize users with the features of the
device and how to use it in a safe and effective manner.

## Quality Control {#quality-control .unnumbered}

We recommend that you provide a description of quality control
recommendations in the labeling and specify what your quality control
material will measure.

## Precautions for use  {#precautions-for-use .unnumbered}

We recommend that you address issues concerning safe use of your assay
with statements in the labeling, such as the following:

Human samples and blood-derived products may be routinely processed with
minimum risk using the procedures described. Human source components of
this device were tested and found negative for anti‑HIV (types 1 and 2),
anti-HCV, and HBsAg by FDA recommended (approved/licensed) tests.
Because no test method can offer complete assurance that laboratory
specimens do not contain HIV, hepatitis B virus, or other infectious
agents, specimens should be handled at the Biosafety Level 2 (BL2) as
recommended for any potentially infectious human serum or blood specimen
in the CDC‑NIH manual, [Biosafety in Microbiological and Biomedical
Laboratories]{.underline}, 3^rd^ Edition, 1993 and NCCLS Approved
Guideline M29-A, Protection of Laboratory Workers from Instrument
Biohazards and Infectious Disease Transmitted by Blood, Body Fluids, and
Tissue.

**Precautions for Interpretations**

We recommend that you address issues concerning patient safety with
statements in the labeling, such as the following:

#### Assay results should be interpreted only in the context of other clinical laboratory findings and the total clinical status of the individual. It has been shown that a viremic window exists with individuals infected with HAV where the individual may be symptomatic for hepatitis, but anti-HAV IgM nonreactive \[Ref. 6\].  {#assay-results-should-be-interpreted-only-in-the-context-of-other-clinical-laboratory-findings-and-the-total-clinical-status-of-the-individual.-it-has-been-shown-that-a-viremic-window-exists-with-individuals-infected-with-hav-where-the-individual-may-be-symptomatic-for-hepatitis-but-anti-hav-igm-nonreactive-ref.-6. .unnumbered}

**References**

  ------- -----------------------------------------------------------------
  \[1\]   Devalle S, de Paula VS, de Oliveira JM, et. al. 2003. Hepatitis A
          virus infection in hepatitis C Brazilian patients, J Infect.
          Aug;47(2):125-128.

  \[2\]   Koff RS, 2001. Risks associated with hepatitis A and hepatitis B
          in patients with hepatitis C, J Clin Gastroenterol.
          Jul;33(1):20-26.

  \[3\]   Vento S, 2000. Fulminant hepatitis associated with hepatitis A
          virus superinfection in patients with chronic hepatitis C, J
          Viral Hepat. May;7 Suppl 1:7-8.

  \[4\]   J.T. Stapleton, 1995. Host immune response to hepatitis A virus.
          Journal of Infectious Diseases 171(S1):S9-S14.

  \[5\]   F.B. Hollinger and S.U. Emerson, 2001. Hepatitis A Virus. In
          [Fields]{.underline} [Virology]{.underline} 4th ed. D.M. Knipe et
          al., eds. Lippincott Williams & Wilkins, Phila., 799-840.

  \[6\]   De Paula VS, Villar LM, Morais LM, et al., 2004. Detection of
          hepatitis A virus RNA in serum during the window period of
          infection, Journal of Clinical Virology (29):254-259.
  ------- -----------------------------------------------------------------

[^1]: Unlike other classification regulations in 21 CFR part 866,
    subpart D, which use the term "reagents" in their titles, FDA is
    using "assays" to refer to this device type because this term more
    accurately reflects the devices within this type.

[^2]: Refer to [http://www.fda..gov/cdrh/ode/indicate.html]()

[^3]: If FDA makes a substantial equivalence determination based on
    acceptance criteria, the subject device should be tested and shown
    to meet these acceptance criteria before being introduced into
    interstate commerce. If the finished device does not meet the
    acceptance criteria and, thus, differs from the device described in
    the cleared 510(k), FDA recommends that submitters apply the same
    criteria used to assess modifications to legally marketed devices
    (21 CFR 807.81(a)(3)) to determine whether marketing of the finished
    device requires clearance of a new 510(k).

[^4]: See Required Elements for a Declaration of Conformity to a
    Recognized Standard **(Screening Checklist for All Premarket
    Notification \[510(K)\] Submissions)**,
    [http://www.fda.gov/cdrh/ode/reqrecstand.html]{.underline}.

[^5]: Although final labeling is not required for 510(k) clearance,
    final labeling must comply with the requirements of 21 CFR part 801
    and 21 CFR 809.10 before a medical device is introduced into
    interstate commerce.