Distribution of In Vitro Diagnostic
Products Labeled for Research Use
Only or Investigational Use Only
Guidance for Industry and Food
and Drug Administration Staff
Document issued on: November 25, 2013
The draft of this document was issued on June 1, 2011.
For questions regarding this document contact Elizabeth Mansfield, by phone at (301)
796-4664, or by email at [email protected].gov. For questions relating to
devices regulated by CBER, contact the Office of Communications, Outreach and
Development, CBER at 301-827-1800 or 800-835-4709.
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
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Preface
Public Comment
You may submit written comments and suggestions at any time for Agency consideration to
the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, rm.
1061, (HFA-305), Rockville, MD, 20852. Submit electronic comments to
http://www.regulations.gov. Identify all comments with the docket number 2011-D-0305.
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/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc
m[insert specific number].htm or http://www.fda.gov/cber/guidelines.htm. You may also
send an e-mail request to [email protected] to receive an electronic copy of the guidance
or send a fax request to 301-847-8149 to receive a hard copy. Please use the document
number 1723 to identify the guidance you are requesting.
Or, contact:
Office of Communication, Outreach and Development, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
Internet:
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/de
fault.htm
Tel: 800-835-4709 or 301-827-1800
E-mail: [email protected]
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Table of Contents
I.
INTRODUCTION....................................................................................................................................... 4
II. REGULATORY REQUIREMENTS FOR RESEARCH USE ONLY AND INVESTIGATIONAL
USE ONLY IVD PRODUCTS .................................................................................................................. 5
III. RESEARCH USE ONLY AND INVESTIGATIONAL USE ONLY IN VITRO DIAGNOSTIC
PRODUCTS ............................................................................................................................................... 7
A. RESEARCH USE ONLY IN VITRO DIAGNOSTIC PRODUCTS ..................................................................... 7
B. INVESTIGATIONAL USE ONLY IN VITRO DIAGNOSTIC PRODUCTS ........................................................ 7
IV. APPROPRIATE LABELING AND DISTRIBUTION PRACTICES FOR RUO AND IUO
PRODUCTS ............................................................................................................................................... 8
A. LABELING OF RUO AND IUO IVD PRODUCTS ....................................................................................... 8
1. Research Use Only Labeling .................................................................................. 8
2. Investigational Use Only Labeling ......................................................................... 8
B. DISTRIBUTION PRACTICES THAT ARE INCONSISTENT WITH RUO/IUO DESIGNATIONS ...................... 9
2. Validation and verification of clinical diagnostic testing using IVD products
labeled RUO or IUO ....................................................................................................... 10
C. OTHER RELEVANT PRACTICES ............................................................................................................. 11
1. Use of a “certification program” .......................................................................... 11
2. Software labeled RUO or IUO ............................................................................. 11
V. FDA’S COMPLIANCE APPROACH ..................................................................................................... 11
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Distribution of In Vitro Diagnostic
Products Labeled for Research Use Only or
Investigational Use Only
Guidance for Industry
and Food and Drug Administration Staff
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.
I. Introduction
FDA is issuing this guidance document to provide the current thinking of the Center for
Devices and Radiological Health (CDRH) and the Center for Biologics Evaluation and
Research (CBER) on when in vitro diagnostic (IVD) products
1
are properly labeled “for
research use only” (RUO) or “for investigational use only” (IUO)
2
. FDA is concerned
that the distribution of unapproved and uncleared IVD products labeled RUO or IUO,
but intended for purposes other than research or investigation (for example, for clinical
diagnostic use
3
), has led, in some cases, to the clinical diagnostic use of products with
unproven performance characteristics, and with manufacturing controls that are
1
“In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of
disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or
prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and
examination of specimens taken from the human body. These products are devices as defined in section 201(h)
of the Federal Food, Drug, and Cosmetic Act (the act), and may also be biological products subject to section
351 of the Public Health Service Act.” Title 21, Code of Federal Regulations (CFR), section 809.3(a).
2
This guidance is only intended to apply to IVD products that have not been approved, cleared or licensed for
any use, and it is not intended to address off-label uses of any approved, cleared or licensed products.
3
Throughout this guidance document, references to “clinical diagnostic use” and “use in clinical diagnosis”
include use in making medical treatment decisions.
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inadequate to ensure consistent manufacturing of the finished product. Use of such tests
for clinical diagnostic purposes may mislead healthcare providers and cause serious
adverse health consequences to patients, who are not aware that they are being
diagnosed with or treated based on the results of tests with research or investigational
products. FDA is issuing this guidance to clarify the requirements applicable to RUO
and IUO IVD products, including that RUO and IUO labeling must be consistent with
the manufacturer’s intended use of the device.
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.
II. Regulatory Requirements for Research Use Only and
Investigational Use Only IVD products
Section 520(g) of the FD&C Act, 21 U.S.C. 360j(g), provides for the exemption of devices
intended for investigational use from certain requirements of the Act if such devices comply
with the procedures and conditions prescribed by that section and by regulation. For
example, devices intended for investigational use that meet applicable requirements may be
exempted from premarket notification and premarket approval requirements of sections 510,
515, 520(g)(2)(A) of the Act (21 U.S.C. 360, 360e, 21 U.S.C. 360j(g)(2)(A)); see also 21
CFR 812.1(a). A product’s intended use refers to the “objective intent” of those responsible
for labeling the product.
4
Intent is determined by such persons’ expressions or may be
shown by the circumstances surrounding the distribution of the article.
5
4
See, 21 CFR 801.4
5
See, id.
Device Investigations Subject to IDE Regulation
FDA's investigational device exemption (IDE) regulation is found at 21 CFR part 812. Under
21 CFR 812.5, investigational devices must bear a label that states the following:
"CAUTION--Investigational device. Limited by Federal (or United States) law to
investigational use." The labeling may not represent that the device is safe or effective for
the purposes for which it is being investigated. 21 CFR 812.5(b). The IDE regulation also
prohibits certain conduct by sponsors and investigators pertaining to the investigation and
distribution of investigational devices, among other practices. See 21 CFR 812.7.
Device Investigations Exempt from IDE Regulation
Investigations of diagnostic devices that meet the criteria at section 812.2(c)(3) are exempt
from the regulations at 21 CFR 812, with the exception of section 812.119. The criteria at
section 812.2(c)(3) include specifying that testing:
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• be non-invasive,
• not require an invasive sampling procedure that presents a significant risk,
• not by design or intention introduce energy into a subject, and
• not be used as a diagnostic procedure without confirmation of the diagnosis by
another, medically established diagnostic product or procedure.
The criteria in section 812.2(c)(3) also include compliance with labeling requirements
section CFR 809.10(c), which exempts shipments and other deliveries of IVDs from certain
labeling requirements if either (1) the device complies with part 812, or (2) the investigation
is not subject to part 812 and one of the following conditions is met:
(i) For a product in the laboratory research phase of development, and not
represented as an effective in vitro diagnostic product, all labeling bears the
statement, prominently placed: "For Research Use Only. Not for use in diagnostic
procedures.''
(ii) For a product being shipped or delivered for product testing prior to full
commercial marketing (for example, for use on specimens derived from humans
to compare the usefulness of the product with other products or procedures which
are in current use or recognized as useful), all labeling bears the statement,
prominently placed: "For Investigational Use Only. The performance
characteristics of this product have not been established.''
For purposes of this guidance document, "labeled RUO" refers to IVD products labeled in
accordance with section 809.10(c)(2)(i); "labeled IUO" refers to IVD products labeled in
accordance with section 809.10(c)(2)(ii) unless otherwise specified. Examples of products
that meet the criteria for these designations are provided in Section III.
Because these products are exempt from most regulatory controls, it is important that they
are not distributed for clinical diagnostic uses.
Mere placement of an RUO or IUO label on an IVD product does not render the device
exempt from otherwise applicable clearance, approval, or other requirements. FDA may
determine that the device is intended for use in clinical diagnosis based on other evidence,
including how the device is marketed.
In general, if evidence shows that an IVD product is inappropriately labeled RUO or IUO,
and that the product does not qualify for an investigational device exemption under 520(g) of
the Act, and is not cleared, approved, or 510(k)-exempt, the device would be misbranded
under sections 502(a) and 502(o) of the Act, 21 U.S.C. 352(a), 352(o), and adulterated under
section 501(f) of the Act, 21 U.S.C. 351(f).
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III. Research Use Only and Investigational Use Only In
Vitro Diagnostic Products
Both RUO and IUO products are IVD products currently under development and not
approved for clinical diagnostic use. Because they are being shipped for investigations
pertaining to product development and not clinical use, these products are exempt from most
regulatory controls including IDE regulation. The term RUO refers to devices that are in the
laboratory phase of development. The term IUO refers to devices that are in the product
testing phase of development.
A. Research Use Only In Vitro Diagnostic Products
An RUO product is an IVD product that is in the laboratory research phase of development
and is being shipped or delivered for an investigation that is not subject to part 812. During
the research phase of development, the focus of manufacturer-initiated studies is typically to
evaluate design, limited-scale performance, and issues such as usability of the test. Some
examples of products FDA would consider to be in this research phase include:
• Tests that are in development to identify test kit methodology, necessary
components, and analytes to be measured.
• Instrumentation, software, or other electrical/mechanical components under
development to determine correct settings, subcomponents, subassemblies, basic
operational characteristics, and possible use methods.
• Reagents under development to determine production methods, purification
levels, packaging needs, shelf life, storage conditions, etc.
FDA also recognizes that there are certain products, such as instruments, systems, and
reagents that are labeled for research use only and intended for use in the conduct of non-
clinical laboratory research with goals other than the development of a commercial IVD
product, i.e., these products are used to carry out research and are not themselves the object
of the research. These include products intended for use in discovering and developing
medical knowledge related to human disease and conditions. For example, instruments and
reagents intended for use in research attempting to isolate a gene linked with a particular
disease may be labeled for research use only when such instruments and reagents are not
intended to produce results for clinical use.
B. Investigational Use Only In Vitro Diagnostic Products
An IUO product is an IVD product that is being shipped or delivered for product testing that
is not subject to 21 CFR part 812 (with the exception of §812.119, Disqualification of
clinical investigator) prior to full commercial marketing (for example, for testing of
specimens derived from humans to compare the usefulness of the product with other products
or procedures which are in current use or recognized as useful). Examples of IVD products
under investigation that FDA considers to fall in this category include those that are being
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evaluated in comparison studies that use archived or fresh specimens to determine
performance characteristics.
IV. Appropriate Labeling and Distribution Practices for
RUO and IUO Products
A. Labeling of RUO and IUO IVD Products
1. Research Use Only Labeling
With respect to IVD products that are appropriately labeled RUO, the RUO labeling is
meant to serve as a warning, to prevent such products from being used in clinical
diagnosis, patient management, or an investigation that is not exempt from 21 CFR part
812. In general, IVD products that are intended for clinical diagnosis or patient
management must be labeled “For In vitro diagnostic use”
6
and be in compliance with
all relevant regulations for In vitro diagnostic devices.
6
21 CFR 809.10(a)(4). Alternatively, some IVD products may be appropriately labeled as analyte specific
reagents (see 21 CFR 864.4020 and 21 CFR 809.10(e)(1)(x) or (xi), or as general purpose reagents (see 21 CFR
864.4010 and 21 CFR 809.10(d)(1)(iv)).
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IVD products intended for investigational use in a manner that is not consistent with an exempted
investigation (see 21 CFR 812.2(c) for a description of exempted investigations) must comply with the
Investigational Device Exemption (IDE) requirements in 21 CFR part 812 in order to be exempt from many
requirements otherwise applicable to medical devices. Instead of being labeled IUO, they must be labeled
An IVD product should not be labeled RUO if it is intended for use in a clinical
investigation subject to 21 CFR part 812 or for clinical diagnostic use outside an
investigation (for example, in clinical diagnosis for standard medical practice).
FDA would consider such an IVD product to be misbranded under section
502(a) of the Act, 21 U.S.C. 352(a), if it were labeled “For Research Use Only”
or otherwise labeled solely for research use, because such labeling would be
false or misleading.
2. Investigational Use Only Labeling
Similarly, with respect to IVD products that are appropriately labeled IUO, the IUO
labeling is meant to serve as a warning that products so labeled should not be used in
clinical diagnosis, patient management, or an investigation that is not exempt from 21
CFR part 812.
An IVD product should not be labeled IUO if it is intended for non-investigational
purposes, such as in clinical diagnostic use outside of an investigation. FDA would
consider such an IVD product to be misbranded under section 502(a) of the Act, 21
U.S.C. 352(a), if it was labeled with the statement: "For Investigational Use Only" or
“Investigational device.”
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“CAUTION—Investigational device. Limited by Federal (or United States) law to investigational use.” 21
CFR 812.5.
8
For the purposes of this guidance document, the term “manufacturer” 21 CFR 806.2(g) is taken as
synonymous with “persons legally responsible for the labeling of devices” 21 CFR 801.4. The term
“manufacturer” is used as a convenience throughout the guidance.
9
See 21 CFR 801.4.
10
Note: FDA is not referring here to generic maintenance support or software updates for an RUO or IUO IVD
product.
9
B. Distribution Practices that are Inconsistent with RUO/IUO
Designations
A product’s intended use refers to the “objective intent” of those legally responsible for
labeling the product
8
, which may be determined by looking at the totality of
circumstances surrounding the distribution of the article.
9
Overt expressions by the
manufacturer, such as those present in labeling and advertising, may be sufficient to show
determine that an IVD product is in appropriately labeled RUO or IUO, when such
expressions demonstrate that the device is actually intended for clinical use despite the
RUO or IUO labeling. Other evidence of the intended use of a product could include the
design of the product, other statements by the manufacturer about the device, and how the
device is sold and distributed by or on behalf of the manufacturer. The following are
examples of evidence of intended uses that, depending on the totality of the
circumstances surrounding the distribution of the article, would appear to conflict with
RUO or IUO labeling:
• Written or verbal statements in any labeling, advertising, or promotion of the IVD
product by or on behalf of the manufacturer, including any performance claims,
instructions for clinical interpretation, clinical information, product names, or
descriptors that claim or suggest that the IVD product may be used for any
clinical diagnostic use, including a clinical investigation subject to part 812. This
may include workshops or presentations that describe clinical uses of products
labeled RUO or IUO that do not include appropriate statements and warnings
about the research or investigational nature of the products;
• Written or verbal statements in any labeling, advertising, or promotion of the IVD
product by or on behalf of the manufacturer that suggest that clinical laboratories
can validate the test through their own procedures and subsequently offer it for
clinical diagnostic use as a laboratory developed test.
• Solicitation of business from clinical laboratories; for example, a
manufacturer who produces only products labeled RUO whose sales force
makes routine calls to clinical laboratories that do not perform research or
clinical studies may be viewed as demonstrating its intent that its products be
used for clinical purposes.
• Provision of certain types of specialized technical support
10
(e.g., assistance in
performing clinical validation) to clinical laboratories.
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Other practices, though not themselves in conflict with RUO or IUO labeling, may
support a finding of a conflicting intended use when accompanied by behavior described
above. For example, when there is a past history of distribution of a product intended for
clinical diagnostic use as an analyte specific reagent (ASR), and the product is now
to and solicitation of business from clinical laboratories, the “new” RUO/IUO labeling is
likely to be inconsistent with the intended use of the manufacturer.
Other practices may or may not indicate an intended use that is consistent with
RUO/IUO labeling, depending on the context. For example:
1. Instructions for use for an IVD product labeled RUO or IUO
FDA may consider all labeling for the product, including the content of the instructions
for use and descriptive language in package inserts provided with the product as
evidence of intended use.
In certain circumstances, such as when the use of an IVD product labeled for research
use only is limited to use in the conduct of laboratory research that is unrelated to the
development of IVDs, providing instructions for correctly using the product in a
research manner (for example, mixing proportions, incubation times, storage
conditions, etc.) would be considered to be consistent with research use only labeling.
However, inclusion of clinical interpretive information, discussion of clinical
significance, or other indications of clinical applicability included with any IVD
products labeled for research use only would suggest that such products are not
intended for research use only, but rather that they are intended for non-research
clinical diagnostic purposes. FDA would consider the provision of such information as
evidence of an intended use that would appear to conflict with research use only
labeling, and requires compliance with all applicable device requirements under the
FD&C Act.
FDA believes that those products that are being distributed for use in the research
phase of IVD development may be unlikely to need instructions for use, as such
products are still in their formative stages, and provision of instructions for using such
products may not always be necessary. If basic instructions for use are needed in order
to properly configure or use the device in the research phase of development, provision
of these may be viewed as consistent with RUO labeling. For IVD products labeled
IUO that are the subject of a clinical investigation by a sponsor other than the
manufacturer, it is acceptable (and perhaps necessary) for the manufacturer to provide
instructions for use to the sponsor of the study using the format described in 21 CFR
809.10(b).
2. Validation and verification of clinical diagnostic testing using IVD products
labeled RUO or IUO
FDA views the activities of a manufacturer that aid the clinical laboratory in validation
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or verification of a test that incorporates RUO or IUO labeled IVD products as
evidence of the manufacturer’s intended use. If the manufacturer of an IVD product
labeled RUO or IUO were to assist in the validation or verification of the performance
of a test for clinical diagnostic use that uses its RUO or IUO labeled IVD, that
assistance would be considered to be evidence of a non-research or non-investigational
intended use. FDA would consider such evidence along with the totality of the
circumstances.
In contrast, the manufacturer of an appropriately labeled RUO or IUO device may
provide support services such as general repair or maintenance, and general non-
diagnostic use-specific technical support, because, in general, these would not
constitute evidence of a non-research or non-investigational intended use.
FDA recommends that manufacturers assess the totality of the circumstances
surrounding the sale and distribution of their RUO and IUO labeled IVD products to
ensure that they are not engaging in practices that conflict with their labeling.
C. Other Relevant Practices
1. Use of a “certification program”
The totality of the circumstances surrounding the distribution and use of an
RUO or IUO product should be considered when assessing its intended use.
User certification programs, where users certify that they will not use RUO/IUO
products in a manner inconsistent with the labeling, would be viewed as one
factor to consider when assessing these circumstances. However, the existence
of a certification program alone would not relieve manufacturers from their
responsibilities to ensure that their labeling and distribution practices for
RUO/IUO products are consistent with the product’s RUO/IUO label.
Software that is a stand-alone IVD product, or a component of or an accessory to
another IVD product, which is labeled for research or investigational use only, may
be distributed for research or investigational use to entities conducting research or
investigations with the software.
V. FDA’s Compliance Approach
Manufacturers must comply with all applicable requirements under the FD&C Act and FDA
regulations for those IVD products that are intended for use in clinical diagnostic
applications. For devices that are not used in research or investigation, these requirements
generally include registration of the manufacturer and listing of the device(s), compliance
with current Good Manufacturing Practices, and reporting of adverse events, among other
general controls. There are also specific requirements for various device types, for example,
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analyte specific reagents. See 21 CFR 809.10(e), 809.30, & 864.4020. While some IVD
products, including some analyte specific reagents, are exempt from premarket notification,
other products require premarket clearance or approval. Where the appropriate regulatory
pathway is unclear, manufacturers are encouraged to discuss the matter with FDA.
When determining whether non-compliance with statutory and regulatory requirements
warrant a regulatory and/or enforcement action, FDA intends to consider the totality of the
circumstances concerning a manufacturer’s sale and distribution of a product labeled as RUO
or IUO.
In general, if evidence shows that an IVD product is inappropriately labeled RUO or IUO,
and that the product does not qualify for an investigational device exemption under 520(g) of
the Act, and is not cleared, approved, or 510(k)-exempt, the device would be misbranded
under sections 502(a) and 502(o) of the Act, 21 U.S.C. 352(a), 352(o), and adulterated under
section 501(f) of the Act, 21 U.S.C. 351(f).
