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**Preface**

**Additional Copies**

Additional copies are available from the Internet at:
<http://www.fda.gov/cdrh/oivd/guidance/1590.pdf>. You may also send an
e-mail request to <dsmica@fda.hhs.gov> to receive an electronic copy of
the guidance or send a fax request to 240-276-3151 to receive a hard
copy. Please use the document number (1590) to identify the guidance you
are requesting.

**Draft Guidance for Industry and FDA Staff Commercially Distributed
Analyte Specific Reagents (ASRs): Frequently Asked Questions**

***This draft guidance, when finalized, will represent the Food and Drug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This draft guidance document is intended to clarify the regulations
regarding commercially distributed analyte specific reagents (ASRs) (21
CFR 809.10(e), 809.30, and 864.4020), and the role and responsibilities
of ASR manufacturers. Below we have listed some frequently asked
questions and FDA's Office of In Vitro Diagnostic Device Evaluation and
Safety's (OIVD's) responses to those questions. Except where otherwise
indicated, the use of the term \"ASR\" in this guidance document refers
to commercially distributed ASRs and the term \"manufacturer\" refers to
manufacturers of commercially distributed ASRs.

FDA is providing this guidance in order to eliminate confusion regarding
particular marketing practices among ASR manufacturers. As noted in this
draft guidance document, ASRs are the building blocks of
laboratory-developed tests. (See section II of this guidance.) ASRs are
defined and classified in a rule codified at 21 CFR 864.4020. With this
draft guidance document, FDA seeks to advise ASR manufacturers that it
views the following practices as being inconsistent with the marketing
of an ASR, as defined under 21 CFR 864.4020:

-   Combining, or promoting for use, a single ASR with another product
    such as other ASRs, general purpose reagents, controls, laboratory
    equipment, software, etc.

-   Promoting an ASR with specific analytical or clinical performance
    claims, instructions for use in a particular test, or instructions
    for validation of a specific test using the ASR.

Some manufacturers have believed that when they combine a Class I ASR,
which is exempt from premarket notification requirements under section
510(l) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C.
360(l), with other products, or with instructions for use in a specific
test, the product remains exempt because of the presence of an ASR.
However, as explained in this guidance, when an ASR is marketed in the
ways described above, FDA views the product as no longer being an ASR
within the meaning of 21 CFR 860.4020 and instead views it as part of a
test system.[^1]

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 ASRs 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.

# FREQUENTLY ASKED QUESTIONS

## I. The ASR Rule {#i.-the-asr-rule .Style-Heading-2-+-Right:--0.03\"-Before:--Auto}

1.  What is the definition of an ASR?

ASRs are defined as "antibodies, both polyclonal and monoclonal,
specific receptor proteins, ligands, nucleic acid sequences, and similar
reagents which, through specific binding or chemical reactions with
substances in a specimen, are intended for use in a diagnostic
application for identification and quantification of an individual
chemical substance or ligand in biological specimens.\" 21 CFR
864.4020(a). ASRs are in vitro diagnostic devices that are regulated by
FDA. They are subject to general controls, including the Quality System
Regulation (QSR) (21 CFR Part 820), as well as the specific provisions
of the ASR regulation (21 CFR 809.10(e), 809.30, 864.4020).

2.  What is the ASR rule?

This guidance document refers to three rules as \"the ASR rule.\" The
rules, published in 1997, include rules that define and classify ASRs
(21 CFR 864.4020), impose restrictions on the sale, distribution, and
use of ASRs (21 CFR 809.30), and establish requirements for ASR labeling
(21 CFR 809.10(e)).

3.  What was the objective of the ASR rule?

The ASR rule was designed to accomplish several policy objectives. These
include ensuring the quality of materials used as components of in-house
laboratory tests, and providing appropriate labeling so that healthcare
users would understand how these tests were being validated. 62 FR
62244. FDA adopted the approach of regulating most ASRs using general
controls and exempting them from premarket notification requirements as
the least burdensome approach. This approach relies primarily on current
Good Manufacturing Practices (cGMPs), medical device reporting, and
labeling requirements, along with the Clinical Laboratory Improvement
Amendments (CLIA), 42 U.S.C. 263a, to adequately control the risks
associated with these devices. 62 FR 62252.

4.  What does the ASR rule require?

The rule classifies most ASRs as Class I devices subject to general
controls under section 513(a)(1)(A) of the Act. The general controls
require ASR manufacturers to register and list their devices, 21 CFR
807.20(a), submit medical device reports (21 CFR Part 803), follow
labeling requirements, 21 CFR 809.10(e), and follow cGMPs, 21 CFR
809.20(b). The rule also restricts the sale, use, distribution,
labeling, advertising and promotion of ASRs. 21 CFR 809.30. One of these
restrictions allows only physicians and other persons authorized by
applicable State law to order in-house tests that are developed using
ASRs. 21 CFR 809.30(f). Another restriction requires the laboratory that
develops an in-house test using an ASR to add a statement disclosing
that the laboratory developed the test and it has not been cleared or
approved by FDA when reporting the test result to the practitioner. 21
CFR 809.30(e).

The restrictions also prohibit advertising and promotional materials for
ASRs from making any claims for clinical or analytical performance. 21
CFR 809.30(d)(4). Consistent with this restriction, the labeling for
Class I, exempt ASRs must bear the statement, \"Analyte Specific
Reagent. Analytical and performance characteristics are not
established.\" 21 CFR 809.10(e)(1)(x). Manufacturers who wish to make
analytical and/or clinical performance claims for a product should
submit an application to FDA for premarket review rather than marketing
the product as an ASR. For example, performance claims might include
statements such as, \"This ASR can be used to quickly and accurately
detect \[a mutation\] associated with \[a disease\].\"

In addition, the rule classifies certain ASRs as Class II or III devices
that are subject to premarket notification or premarket approval
application requirements in addition to the general controls described
above.

[]{.mark}

5.  Are some ASRs Class II or Class III, requiring a premarket
    submission?

Yes. Although most ASRs are Class I, there are some ASRs that are Class
II and Class III and that must be cleared or approved by FDA before they
can be marketed in the United States. 21 CFR 864.4020. FDA classifies
medical devices, including diagnostic devices such as ASRs, into Class
I, II, or III according to the level of regulatory control that is
necessary to provide a reasonable assurance of safety and effectiveness.
These classifications include consideration of the level of risk
associated with the device. 21 U.S.C. 360c. The classification of an ASR
determines the appropriate premarket process.

An ASR is a Class II device if the reagent is used as a component in a
blood banking test of a type that has been classified as a Class II
device (e.g., certain cytomegalovirus serological and treponema pallidum
nontreponemal test reagents). 21 CFR 864.4020(b)(2).

An ASR is a Class III device if the reagent is intended as a component
in tests intended either:

-   to diagnose a contagious condition that is highly likely to result
    in a fatal outcome and prompt, accurate diagnosis offers the
    opportunity to mitigate the public health impact of the condition
    (e.g., human immunodeficiency virus (HIV/AIDS) or tuberculosis
    (TB)); or

-   for use in donor screening for conditions for which FDA has
    recommended or required testing in order to safeguard the blood
    supply or establish the safe use of blood and blood products (e.g.,
    tests for hepatitis or for identifying blood groups). 21 CFR
    864.4020(b)(3).

6.  How does a manufacturer know whether its device is an ASR?

We recommend that ASR manufacturers consult this document for guidance
on whether their product is or is not within the scope of the ASR rule.
Manufacturers should contact FDA if they are unsure about the
classification of their device to discuss any applicable regulatory
requirements. Manufacturers who wish to obtain FDA advice on this matter
in advance of marketing may consult with OIVD. 

## II. What Meets the ASR Definition? {#ii.-what-meets-the-asr-definition .Style-Heading-2-+-Right:--0.03\"-Before:--Auto}

The ASR definition has given rise to confusion about which products fall
within and outside of its bounds. Some of this confusion arises because
a product that might in some circumstances be an ASR, will no longer be
one due to its marketing and claims.

In the preamble to the ASR rule, FDA stated that ASRs may be thought of
as the \"active ingredients\" of tests that are used to identify one
specific disease or condition. ASRs are purchased by manufacturers who
use them as components of tests that have been cleared or approved by
FDA and also by clinical laboratories that use the ASRs to develop
in-house tests used exclusively by that laboratory. 62 FR 62243, 62244.
This is in contrast with what the preamble referred to as a \"kit or
system for \'in vitro diagnostic use\'\" that has a proposed intended
use, indications for use, instructions for use, and performance
characteristics. 62 FR 62243, 62250. FDA designed the ASR rule to
require that ASR manufacturers take certain actions, such as following
cGMPs, to help ensure the safety and effectiveness of their devices. A
premise underlying the rule, however, is that laboratories, rather than
ASR manufacturers, develop the test in which the ASR is used and provide
all necessary verification and validation.

Based upon this description, together with the ASR definition, FDA views
an ASR as having the following characteristics:

-   a single moiety;

-   a single endpoint;

-   no instructions or performance claims; and

-   not promoted for use on specific instruments or in specific tests or
    test systems.

7.  What are some examples of entities that FDA considers to be ASRs?

Examples of molecules that are ASRs are a single antibody (e.g., an
anti-troponin I antibody), a single nucleotide primer (e.g., a forward
primer for amplification of the ΔF508 locus of the gene encoding the
cystic fibrosis transmembrane regulator (CFTR)), and a single purified
protein or peptide (e.g., purified estrogen receptor protein or purified
B-type natriuretic peptide). The above-listed examples would not be
considered ASRs if they are marketed with clinical or analytical
performance claims (e.g., cystic fibrosis genotyping, identification of
cardiac risk).

8.  What are some examples of entities that FDA does not consider to be
    ASRs?

-   Multiple moieties (e.g., antibodies, probes, primers) bundled
    together in a pre-configured or optimized manner so that they are
    intended to identify and quantify more than one chemical substance
    or ligand. Such products are not ASRs because ASRs are defined as
    intended for use in \"identification and quantification of an
    *individual* chemical substance or ligand in biological specimens.\"
    21 CFR 864.4020(a) (emphasis added). As a result, FDA considers such
    products to be test systems, rather than ASRs. This means that
    products that might be ASRs when marketed individually, would not be
    considered ASRs when combined or multiplexed because they are no
    longer intended to identify an \"individual chemical substance.\"
    ASRs are intended to be individual building blocks of tests that a
    laboratory develops. When a manufacturer combines ASRs, it has taken
    steps to build a particular test.

-   Test systems. FDA considers a product a test system rather than an
    ASR when it includes more than a single ASR (i.e., it includes some
    or all of the products needed to conduct a particular test such as
    more than one ASR, general reagents, controls, equipment, software,
    etc.) and/or has instructions for use.

-   Control material.

-   Products that have specific performance claims, or procedural
    instructions, or interpretations for use.

-   Reagents that are extensively processed (e.g., arrayed on beads).
    This type of modification is an optimization of the reagent to
    create a particular intended use that is more specific than the
    broad intended use described in the ASR definition. 21 CFR
    864.4020(a).

-   Reagents offered with software for interpretation of results.

-   Products that do not meet the ASR definition, such as software for
    interpretation of assay results, or microarrays.

9.  How do General Purpose Reagents compare to ASRs?

> A General Purpose Reagent (GPR) is "a chemical reagent that has
> general laboratory application, that is used to collect, prepare, and
> examine specimens from the human body for diagnostic purposes, and
> that is not labeled or otherwise intended for a specific diagnostic
> application." 21 CFR 864.4010(a). Like ASRs, GPRs are not labeled for
> a specific clinical or diagnostic use. Because GPRs are not
> analyte-specific, they should be able to be combined with, or used in
> conjunction with more than one ASR. In contrast, as stated above, an
> ASR is a specific chemical component, probe, or antibody that can
> detect an individual chemical substance or ligand. An ASR is
> considered the "active ingredient" or "building block" of a
> laboratory-developed test.

## III. Manufacturer Marketing Practices

10. To whom can manufacturers sell ASRs?

ASRs may only be sold to:

-   in vitro diagnostic manufacturers;

-   clinical laboratories regulated under the Clinical Laboratory
    Improvement Amendments of 1988 (CLIA), as qualified to perform high
    complexity testing or clinical laboratories regulated under VHA
    Directive 1106; and

-   organizations that use the reagents to make tests for purposes other
    than providing diagnostic information to patients and practitioners,
    e.g., forensic, academic, research and other nonclinical
    laboratories.

21 CFR 809.30 (b).

11. **Can a manufacturer or distributor promote specific ASRs and GPRs
    for use together in developing a test?**

No. As explained above, ASRs are considered individual "building blocks"
of laboratory tests and GPRs may not be intended for a specific
diagnostic application. 21 CFR 864.4010, 864.4020. Although a GPR may
consist of a single substance or a formulation of multiple substances as
defined by 21 CFR 864.4010, it should be intended for general rather
than specific use. A product that is promoted for use with an ASR is
intended for a specific diagnostic use with that ASR and therefore would
not meet the GPR definition of being for \"general laboratory
application.\" Similarly, a product that is promoted for use with a
specific GPR is intended for a particular intended use rather than as an
ASR, which is a building block of laboratory-developed tests. Therefore,
a manufacturer who wishes to market its products as GPRs or ASRs should
not promote or sell them together, including in test system
configurations.

We recommend that manufacturers who wish to market products as ASRs,
rather than as test systems, avoid listing ASRs, GPRs, and/or controls
in catalogues, web sites, and other promotional materials, in small
groupings that suggest these devices should be used together for a
specific purpose. For example, primers specific for Factor V, Factor II,
and MTHFR listed together with complementary probes and control material
suggest that this group of reagents may be used together as a type of
thrombophilia panel. Manufacturers who wish to promote products together
in this manner should submit a PMA or 510(k) to FDA for approval or
clearance of a test system.

To avoid promoting products as test systems rather than as separate ASRs
and GPRs, we recommend that manufacturers list ASRs and GPRs in a
fashion that is not associated with use in a particular test (e.g.,
alphabetically, or by reagent type \[primers together, buffers
together\]).

12. Can the manufacturer include instructions with an ASR?

ASR manufacturers should not provide such instructions with an ASR. As
explained above, FDA views reagents that are sold with instructions for
developing or performing a test as test systems rather than as ASRs
because an ASR is a building block for laboratory-developed tests and
has no analytical or clinical performance claims. 21 CFR
809.10(e)(1)(x), 809.30(d)(4). Instructions for use of an ASR in a
particular test constitute a claim that, when used as directed, the ASR
will perform to detect a particular chemical substance or ligand.

On the other hand, instructions for storage and handling of an ASR must
be provided. 21 CFR 809.10(e)(1)(vi). In addition, scientific
information may be included on chemical/molecular composition, nucleic
acid sequence, binding affinity, cross-reactivities, known mutations
associated with the sequence, and interaction with substances of known
clinical significance. 21 CFR 809.10(e)(1)(iv).

13. Can a manufacturer or distributor tell a laboratory which ASRs are
    useful for a particular application, for example, which monoclonal
    antibodies or probes are useful for leukemia or lymphoma testing?

Manufacturers and distributors should not make claims to physicians or
laboratories regarding analytical or clinical performance for ASRs. The
laboratories, not the manufacturers or distributors, should be
responsible for the performance of the test. 21 CFR 809.30(d)(4). In
addition, manufacturers should take care to avoid names for their ASRs
that describe a specific clinical use.

ASR labeling may indicate the affinity of the reagent, such as
\"anti-estrogen receptor antibody" or "ΔF508 CFTR nucleic acid probe.\"
Other similar information, such as the affinity, target, or sequence of
a DNA probe or a protein sequence, may also be provided because it
describes what the ASR is specific for but does not claim to produce a
particular clinical or analytical result. But a name such as "Cystic
Fibrosis ASR" describes a specific clinical use for the product and FDA,
therefore, would not consider such a product to be an ASR.

[]{.mark}

14. Can an ASR manufacturer supply quality control materials/reagents
    that can be used with an ASR?

Yes, but these materials should be promoted independently of specific
ASRs. Marketing such materials with an ASR may make it appear that the
manufacturer is actually marketing a test system, which could trigger
premarket review requirements. Quality control materials should be
promoted and sold using existing FDA classifications for quality control
material. (e.g., 21 CFR 862.1660, 862.3280, 864.8625)

15. Can a manufacturer or distributor market software for use with an
    ASR?

If a manufacturer chooses to market software for use with its product,
then the products together would be considered a test system, rather
than an ASR. ASR manufacturers should not promote or sell software for
use with a particular ASR.

16. What types of instrumentation can manufacturers promote for use with
    laboratory-developed tests?

Manufacturers should not promote closed system laboratory instruments
(i.e., when the user does not have the ability to modify instrument
settings, or the design of the instrument allows only a specific
proprietary reagent technology or assay method to be used) for use in
conjunction with particular ASRs. FDA would consider promotion of such
instrumentation with a specific ASR to be promotion of a test system.

In contrast, open system instruments that have user-defined
capabilities, which allow the user to define, optimize, and validate the
test performance characteristics and interpretation criteria, may be
promoted for use generally in laboratory-developed tests. Examples of
these instruments include spectrophotometers, HPLC, and flow cytometers.
The instrumentation should be able to run various assays, allow
parameter modification, or have a user interface that the laboratory can
modify to define specific parameters for their laboratory-developed
assay. If instrumentation is used, the laboratory should select the
instrumentation and validate the performance of the laboratory-developed
assay on that instrument.

17. Can the ASR manufacturer help with the verification of performance
    specifications of a test that utilizes its ASR?

Under the CLIA regulations, the laboratory must conduct verification of
performance specifications. 42 CFR 493.1213. This validation by the
laboratory is the minimum required under CLIA for the laboratory to
generate clinical results for tests of high complexity. If a
manufacturer or distributor wishes to market its product as an ASR, it
should not assist with the validation of a laboratory-developed test
using its specific ASR.

18. What type of information about a particular ASR can an ASR
    manufacturer provide to a laboratory?

A manufacturer may provide laboratories with information, including
peer-reviewed and published/presented literature, limited to
characteristics of the ASR itself. If a manufacturer intends to market
its products as ASRs, it should not promote its products with literature
and other materials that include information on use of the ASR in a
specific test or test system. This would include information regarding
an ASR\'s clinical utility and clinical performance as well as specific
instructions-for-use and validation protocols. FDA views this type of
information, when provided by the manufacturer, as evidence of intent to
market a test system with instructions for use and validation. FDA would
not view a product that is promoted with such information as an ASR.

## IV. Research and Investigational Use of ASRs

19. Can ASRs be used for research?

Yes, ASRs can be used for research applications. The ASR requirements,
including the need for the laboratory report disclaimer, apply only to
clinical diagnostic use of these products and not to research
applications. 21 CFR 864.4020(a)(2).

20. How is the ASR rule related to in vitro diagnostic products labeled
    for research or investigational use?

Products labeled for research use only (RUO) or investigational use only
(IUO) are IVDs in different stages of development.

-   FDA considers RUO products to be products that are in the laboratory
    research phase of development, that is, either basic research or the
    initial search for potential clinical utility, and not represented
    as an effective in vitro diagnostic product. During this phase, the
    focus of manufacturer-initiated studies is typically to evaluate
    limited-scale performance and potential clinical or informational
    usefulness of the test. These products must be labeled "For Research
    Use Only. Not for use in diagnostic procedures." as required under
    21 CFR 809.10 (c)(2)(i).

-   FDA considers IUO products to be products that are in the clinical
    investigation phase of development. They may be exempt from the
    investigational device (IDE) requirements of 21 CFR Part 812 (21 CFR
    812.2(c)), or may be regulated under 21 CFR Part 812 as either a
    non-significant risk device or a significant risk device. Diagnostic
    devices exempt from IDE requirements cannot be used for human
    clinical diagnosis unless the diagnosis is being confirmed by
    another, medically-established diagnostic product or procedure (21
    CFR 812.2(c)(3)(iv)). During this phase, the safety and
    effectiveness of the product are being studied; i.e., the clinical
    performance characteristics and expected values are being determined
    in the intended patient population(s). These products must be
    labeled, \"For Investigational Use Only. The performance
    characteristics of this product have not been established." 21 CFR
    809.10(c)(2)(ii).

21. What is the difference in GMP requirements for manufacturers of an
    ASR versus an RUO reagent?

Manufacturers establish and follow cGMPs, as established in the quality
system regulation, to help ensure that their products are manufactured
under controlled conditions that assure the devices meet consistent
specifications across lots and over time. ASRs must be manufactured
following cGMPs. 21 CFR 809.20. FDA does not expect RUO reagents to be
manufactured in compliance with cGMPs because products labeled as RUO
reagents cannot be used as clinical diagnostic products. 21 CFR
809.10(c)(2)(i).

[^1]: FDA\'s use of the term \"test system\" in this guidance document
    is not linked to definitions in 42 CFR Part 493. See question 8 for
    discussion of what FDA considers a \"test system.\"