**Guidance for Industry**

**and FDA Staff**

**Class II Special Controls Guidance Document: Instrumentation for
Clinical Multiplex Test Systems**

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

For questions regarding this document contact Courtney Harper at
240-276-0443 or by email at courtney.harper@fda.hhs.gov.

![](media/image1.png)

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

**Food and Drug Administration**

**Center for Devices and Radiological Health**

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

**Division of Chemistry and Toxicology Devices**

**Preface**

**Public Comment**

> Written comments and suggestions may be submitted at any time for
> Agency consideration to the Division of Dockets Management, Food and
> Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305),
> Rockville, MD, 20852. Alternatively, electronic comments may be
> submitted to <http://www.fda.gov/dockets/ecomments>. When submitting
> comments, please refer to Docket No. 2005D-0069. Comments may not be
> acted upon by the Agency until the document is next revised or
> updated.

**Additional Copies**

> Additional copies are available from the Internet at:
> [http://www.fda.gov/cdrh/oivd/guidance/1546.pdf](http://www.fda.gov/cdrh/oivd/guidance/xxxx.pdf),
> or to receive this document by 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 (1546)
> followed by the pound sign (#). Follow the remaining voice prompts to
> complete your request. For questions regarding the use or
> interpretation of this guidance contact: Courtney Harper at
> 240-276-0443 or by email at courtney.harper@fda.hhs.gov.
>
> **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 9](#device-description)

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

[8. Software 11](#software)

[9. Labeling 12](#labeling)

**Guidance for Industry and FDA Staff**

**Class II Special Controls Guidance Document: Instrumentation for
Clinical Multiplex Test Systems**

***This guidance represents 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 guidance document was developed as a special controls guidance to
support the classification of instrumentation for clinical multiplex
test systems into class II (special controls). This type of device is
intended to measure and sort multiple signals generated by an assay from
a clinical sample. This instrumentation is used with a specific assay to
measure multiple similar analytes that establish a single indicator to
aid in diagnosis. Such instrumentation may be compatible with more than
one specific assay. The device includes a signal reader unit, and may
also integrate reagent handling, hybridization, washing, dedicated
instrument control, and other hardware components, as well as raw data
storage mechanisms, data acquisition software, and software to process
detected signals.

This guidance is relevant to instrumentation for use with the subset of
multiplex tests that measure multiple similar analytes that establish a
single indicator to aid in diagnosis. Examples of such tests include an
assay that analyzes multiple single nucleotide polymorphisms (SNPs) to
determine a patient\'s genotype, or an assay that analyzes multiple
alleles to determine a patient\'s genotype. Depending on the nature of
the multiplex test for use with the instrumentation, the instrumentation
could aid in clinical applications, such as screening or diagnosis of
disease, drug selection and dosing, patient management, and the
assessment of disease progression and regression.

A specific multiplex assay or test that is intended to be run on
instrumentation for clinical multiplex test systems is considered a
separate device, and does not fall under the scope of 21 CFR 862.2570.
Such specific assays often include software that is used to process the
particular signal measurements that result from the specific assay, as
well as reagents for carrying out the test. Such software is regulated
as part of the specific assay to which it pertains. However, as noted
above, instrumentation for clinical multiplex test systems does include
its own software, including data acquisition software and software to
process detected signal, which are used with any assay run on that
instrumentation.

Manufacturers of instrumentation for clinical multiplex test systems
should only claim diagnostic applications for their device that are
associated with legally marketed multiplex assays.

This guidance is issued in conjunction with a Federal Register notice
announcing the classification of instrumentation for clinical multiplex
test systems. Any firm submitting a premarket notification (510(k)) for
a device of this type will need to address the issues covered in this
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, guidance documents
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 guidance
documents means that something is suggested or recommended, but not
required.

**The Least Burdensome Approach**

The issues identified in this guidance document represent those that we
believe should be addressed before your device can be marketed. In
developing the guidance, we carefully considered the relevant statutory
criteria for Agency decision-making. We also considered the burden that
may be incurred in your attempt to follow the statutory and regulatory
criteria in the manner suggested by the guidance and in your attempt to
address the issues we have identified. We believe that we have
considered the least burdensome approach to resolving the issues
presented in the guidance document. If, however, you believe that there
is a less burdensome way to address the issues, you should follow the
procedures outlined in the document, "A Suggested Approach to Resolving
Least Burdensome Issues." It is available on our Center web page at:
<http://www.fda.gov/cdrh/modact/leastburdensome.html>.

# Background

> FDA believes that special controls, when combined with the general
> controls, provide reasonable assurance of the safety and effectiveness
> of instrumentation for clinical multiplex test systems. 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 807 Subpart E, (2) address the specific risks to health
> associated with the device identified in this guidance, and (3) obtain
> a substantial equivalence determination from FDA before marketing the
> device.

This guidance document identifies the classification regulation and
product code for instrumentation for clinical multiplex test systems.
(Refer to Section 4 -- Scope.) In addition, other sections of this
guidance document identify the risks to health and describe measures
that, if followed by manufacturers and combined with the general
controls, will generally address the risks associated with these devices
and lead to a timely premarket notification (510(k)) review and
clearance. This document supplements other FDA documents regarding the
specific content requirements of a premarket notification submission.
You should also refer to 21 CFR 807.87 and other FDA documents on this
topic, such as the **510(k) Manual - Premarket Notification: 510(k) -
Regulatory Requirements for Medical Devices**,
<http://www.fda.gov/cdrh/manual/510kprt1.html.>

As explained in "**The New 510(k) Paradigm - Alternate Approaches to
Demonstrating Substantial Equivalence in Premarket Notifications; Final
Guidance**[^1]," a manufacturer may submit either a Traditional 510(k)
or an Abbreviated 510(k). FDA believes an Abbreviated 510(k) provides
the least burdensome means of demonstrating substantial equivalence for
a new device, particularly when FDA has issued a guidance document that
provides recommendations on what should be addressed in a submission for
the device. Alternatively, 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 the
methods or tests used. The report should also include 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 21 CFR 807.87 as well as some other items
that we recommend you generally include in an Abbreviated 510(k).

> **Coversheet**
>
> The coversheet should prominently identify the submission as an
> Abbreviated 510(k) and cite the title of this guidance document.
>
> **Proposed labeling**
>
> Proposed labeling should be sufficient to describe the device, its
> intended use, and the directions for its use. (Refer to Section 9 for
> specific information that you should include in the labeling for this
> type of device.)
>
> **Summary report**

We recommend that the summary report contain the following:

-   A description of the device and its intended use. You should also
    submit an \"indications for use\" enclosure.[^2] (Refer to Section 6
    for specific information that you should include in the description
    for this type of device.)

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-   A description of the device design. We recommend that the
    description include a complete discussion of the performance
    specifications and, when appropriate, detailed, labeled drawings of
    the device.

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-   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.)

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-   A discussion of the device characteristics that address the risks
    identified in this class II special controls guidance document, as
    well as any additional risks identified in your risk analysis.

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-   A brief description of the test method(s) you have used or intend to
    use to address each performance aspect identified in Sections 6 and
    7 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, 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>.

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
premarket notification for instrumentation for clinical multiplex test
systems.

# Scope

The scope of this document is limited to the following devices as
described in 21 CFR 862.2570 (product code NSU):

[21 CFR 862.2570]{.underline} Instrumentation for clinical multiplex
test systems.

Instrumentation for clinical multiplex test systems is a device intended
to measure and sort multiple signals generated by an assay from a
clinical sample. This instrumentation is used with a specific assay to
measure multiple similar analytes that establish a single indicator to
aid in diagnosis. Such instrumentation may be compatible with more than
one specific assay. The device includes a signal reader unit, and may
also integrate reagent handling, hybridization, washing, dedicated
instrument control, and other hardware components, as well as raw data
storage mechanisms, data acquisition software, and software to process
detected signals.

A specific multiplex assay or test that is intended to be run on
instrumentation for clinical multiplex test systems is considered a
separate device. This guidance document does not address performance
characteristics for such assays. The guidance document, *Replacement
Reagent and Instrument Family Policy*, (available at
http://www.fda.gov/cdrh/oivd/guidance/950.pdf) does not apply to
instrumentation for clinical multiplex test systems.

# Risks to Health

FDA has identified the risks to health associated with this type of
device as potentially inaccurate results, or inaccurate reports, which
may lead to incorrect diagnoses or patient evaluation that could result
in inappropriate and possibly dangerous patient management.
Specifically, failure of instrument components, including reagent
introduction and hybridization systems, signal detection mechanisms,
instrument control and data acquisition software, and raw data storage
mechanisms could lead to inaccurate results. Likewise, failure of data
management and database software could result in the compromise of
patient identification or mis-matched results. Furthermore, failure of
the instrumentation to generate any results at all can deny or delay
beneficial, appropriate therapies.

In the table below, FDA has identified the risks to health generally
associated with the use of instrumentation for clinical multiplex test
systems, as addressed in this document. The measures recommended to
mitigate these identified risks are given in this guidance document, as
shown in the table below. We recommend that you conduct a risk analysis,
before 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 a particular 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

  Inaccurate or absent results due to Sections 7 and 9
  failure of instrumentation          
  components                          

  Inaccurate or absent results or     Section 8
  reports due to failure of data      
  management and database software    
  ----------------------------------- -----------------------------------

# Device Description

In your 510(k), you should identify the regulation, the product code,
and a legally marketed predicate device. In order to help FDA
efficiently review all the aspects of your device compared with the
predicate, you should include a table that outlines the similarities and
differences between the predicate and your device.

Key issues in the review of a new device are the specific intended use,
the type of specimens tested, and the technology utilized. You may
submit appropriate peer-reviewed literature references relevant to the
technology of the device in addition to the descriptive information to
adequately describe the new instrumentation. You should include the
following descriptive information to adequately characterize the new
instrumentation for clinical multiplex test systems.

*Intended Use*

You should clearly describe the intended use of the device. Some
instrumentation may have multiple intended uses. For example, the
instrumentation may be able to measure more than one type of molecule
(e.g., DNA or RNA). We recommend a separate application for each
intended use that requires unique and separate supporting studies. You
should consult the appropriate review divisions in the Office of In
Vitro Diagnostic Device Evaluation and Safety for advice on submitting
instrumentation with multiple intended uses.

*Device description*

You should identify the legally marketed assay or assays to be used with
the instrumentation. The multiplex assay for use on the instrument may
be submitted in the same 510(k) as the instrument, or in a separate
510(k).

We recommend that you provide a thorough explanation of all aspects of
the device methodology. This could include, but is not limited to, the
following:

-   How the instrument is designed to carry out its functions related to
    amplification, hybridization, or signal detection.

-   Additional instrument components that you provided, or recommend for
    use, and their function in the system.

-   The sample type(s) that may be run on the instrumentation.

-   Types of output generated by the instrumentation and system
    parameters (e.g., reading ranges).

-   Related peer-reviewed literature references, if applicable.

# Performance Characteristics 

*Precision/Reproducibility*

We recommend that you characterize the reproducibility of the
instrumentation for clinical multiplex test systems using a
well-characterized sample with positive and negative control assays. We
recommend that you design the study to assess overall instrumentation
performance, e.g., sample processing consistency, scanner drift. You
should justify statistically the sample size for the reproducibility
study. You should include two or more operators and three or more
instruments in the study, and ensure that samples are masked and
expected results are unknown to operators. For instrumentation that can
be used to run more than one type of assay (e.g., genotyping and
expression arrays), you should demonstrate reproducible performance for
each type of assay. You should provide the protocol (including
statistical methods), results and analysis for between-assay,
between-scan, between-instrument, between-operator, or other
evaluations, as appropriate. If applicable, we recommend that you report
the following types of information.

-   Coefficients of variation (CV) with confidence intervals, for
    between- instruments, operators, device lots, and intra- and
    inter-assay, as appropriate. If the device is used with a
    micro-array type of assay, intra- and inter-assay evaluations are
    especially important to establish reliability of the device.

-   Pairwise correlation coefficients, scatter plots, and ANOVA analysis
    of data from all relevant elements of the reproducibility study. You
    should also report any additional metrics, as appropriate.

-   Any bias that you observe during your reproducibility studies, and
    an explanation to account for the bias.

You should select materials and design your reproducibility evaluation
in a way that will produce sufficient reproducibility data across all
aspects of the instrumentation and across all dimensions (including
time). Depending on the design of the assays intended to be run on the
instrumentation, this may include attention to features such as probes,
substrates, and samples. To fully investigate signal detection
uniformity and stability, you should use assays with signal features
that show minimal change with exposure to signal detection (e.g., signal
deterioration) and time. For platforms that contain sample preparation
steps such as amplification, hybridization, or washing, you should
design a reproducibility protocol that will stress the instrumentation
to an appropriate degree, i.e., you should not use an assay system that
is so robust as to obscure changes in sample integrity that may occur
during preparation or assay steps.

*Method Comparison*

If appropriate, you may evaluate the performance of your instrumentation
against your predicate device. The results are usually reported as
percent agreement. In cases where you cannot directly compare
performance characteristics of your device to those of your predicate,
FDA believes that the best way to test performance is to compare to a
gold standard method, when available.

*Calibration*

You should develop and recommend a calibration program and maintenance
schedule for each portion of the instrumentation.

# Software

You should submit software documentation for the data acquisition
software or other software component of your instrumentation that is
detailed in accordance with the level of concern (See: *Guidance for the
Content of Premarket Submissions for Software Contained in Medical
Devices* (<http://www.fda.gov/cdrh/ode/57.html>)). You should determine
the Level of Concern prior to the mitigation of hazards. In vitro
diagnostic devices of this type are typically considered a moderate
level of concern, because software flaws could indirectly affect the
patient and potentially result in injury (through the action or inaction
of a health care provider).

We consider the following points to be important elements in preparing
software documentation for FDA review:

-   You should fully describe the software design. You should not
    include software utilities that are specifically designed to support
    uses beyond those of the legally marketed assays identified in your
    510(k). You should also consider privacy and security issues in your
    design. Information on some of these issues may be found at the
    following website regarding the Health Insurance Portability and
    Accountability Act (HIPAA) http://aspe.os.dhhs.gov/admnsimp.

-   You should submit a hazard analysis based on critical thinking about
    the device design and the impact of any failure of subsystem
    components, such as signal detection and analysis, data storage,
    system communications and cybersecurity in relationship to incorrect
    patient reports, instrument failures, and operator safety.

-   You should complete verification and validation (V&V) activities for
    the version of software that will be utilized for the submission in
    demonstrating substantial equivalence.

-   If the information you include in the 510(k) is based on a version
    other than the release version, you should identify all differences
    and detail how these differences (including any unresolved
    anomalies) impact the safety and effectiveness of the device.

Below are additional references to help you develop and maintain your
device under good software life cycle practices consistent with FDA
regulations.

-   General Principles of Software Validation; Final Guidance for
    Industry and FDA Staff; available on the FDA Web site at:
    http://www.fda.gov/cdrh/ode/510kmod.pdf.

-   Guidance for Off-the-Shelf Software Use in Medical Devices; Final
    Guidance for Industry, FDA Reviewers and Compliance; available on
    the FDA Web site at: http://www.fda.gov/cdrh/ode/guidance/585.pdf.

-   21 CFR 820.30 Subpart C -- Design Controls of the Quality System
    Regulation.

-   ISO 14971-1; Medical devices - Risk management - Part 1: Application
    of risk analysis.

-   AAMI SW68:2001; Medical device software - Software life cycle
    processes.

# 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 preparing proposed labeling
that satisfies the requirements of 21 CFR 807.87(e). Although final
labeling is not required for 510(k) clearance, final labeling must
comply with the requirements of 21 CFR 809.10 before an in vitro
diagnostic device is introduced into interstate commerce.

*Performance Characteristics*

When describing performance characteristics of the device, we recommend
that you describe all relevant aspects of your protocol, including
materials used and results. We also recommend that you provide graphic
representations of the results.

*User Manual*

We recommend that you provide a user manual that addresses all
components of the instrumentation for clinical multiplex test systems.
Your user manual should provide an adequate description of the role of
the software, the user interface with the software, as well as results
of performance testing to demonstrate that the software functions as
designed. We recommend pictorial representations of computer screens,
graphical user interfaces (GUIs), and other elements that aid the user
in correctly using the software.

The user manual, where possible, should also include descriptions of how
the user can recognize incorrect operation or failure of the
instrumentation, and a troubleshooting guide.

[^1]: <http://www.fda.gov/cdrh/ode/parad510.html>

[^2]: Refer to
    [http://www.fda.gov/cdrh/ode/indicate.html](http://www.fda.gov/cdrh/ode/indicate.pdf)
    for the recommended format.

[^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>.