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 elizabeth.mansfield@fda.hhs.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 
          
 
 
 
       
Center for Biologics Evaluation and Research 
  Contains Non-binding Recommendations 
 
 
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 dsmica@fda.hhs.gov 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: ocod@fda.hhs.gov  
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  Contains Non-binding Recommendations 
 
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 
1.  Instructions for use for an IVD product labeled RUO or IUO ............................. 10 
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. FDAS COMPLIANCE APPROACH ..................................................................................................... 11 
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  Contains Non-binding Recommendations 
 
  
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) products1 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 use3), 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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  Contains Non-binding Recommendations 
 
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 manufacturers 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 products 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   
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:  
                                                 
4 See, 21 CFR 801.4 
5 See, id.  
 
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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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  Contains Non-binding Recommendations 
 
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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  Contains Non-binding Recommendations 
 
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 use6 and be in compliance with 
all relevant regulations for In vitro diagnostic devices. 
 
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.7 
                                                 
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)). 
7 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  
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B.  Distribution Practices that are Inconsistent with RUO/IUO 
Designations 
 
A products intended use refers to the objective intent of those legally responsible for 
labeling the product8, 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.  
 
                                                                                                                                                       
CAUTIONInvestigational 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. 
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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 
labeled as RUO or IUO, without any change in distribution practices such as advertising 
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 manufacturers 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 products RUO/IUO label.  
 
2.  Software labeled RUO or IUO 
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.  FDAs 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 manufacturers 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).   
12