Molecular Diagnostic Instruments 
with Combined Functions  
 
 
Guidance for Industry and Food 
and Drug Administration Staff    
 
 
Document issued on November 12, 2014.  
The draft of this document was issued on April 9, 2013. 
 
For questions about this document, contact the Division of Microbiological Devices in 
CDRHs OIR and Andrew Grove, PhD, 301-796-6198, Andrew.grove@fda.hhs.gov. 
For questions for CBER, contact the Office of Communication, Outreach and Development 
(OCOD) by calling 1-800-835-4709 or  240-402-7800. 
 
 
 
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 Microbiology Devices 
 
 
Center for Biologics Evaluation and Research 
 
 
 
 
  Contains Nonbinding Recommendations 
 
 
Preface 
Public Comment 
You may submit electronic comments and suggestions at any time for Agency consideration to 
http://www.regulations.gov . Submit written comments to the Division of Dockets 
Management, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), 
Rockville, MD 20852. Identify all comments with the docket number FDA-2013-D-0258. 
Comments may not be acted upon by the Agency until the document is next revised or updated. 
Additional Copies 
CDRH 
Additional copies are available from the Internet. You may also send an e-mail request to 
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document 
number 1763 to identify the guidance you are requesting. 
CBER 
Additional copies are available from the Center for Biologics Evaluation and Research 
(CBER) by written request, Office of Communication, Outreach and Development (OCOD) 
10903 New Hampshire Avenue, Building 71, Room 3128,  Silver Spring, MD 20993-0002, 
or by calling 1-800-835-4709 or  240-402-7800, or by e-mail at ocod@fda.hhs.gov or from 
the Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ 
Guidances/ default.htm.  
    Contains Nonbinding Recommendations 
 
 
Molecular Diagnostic Instruments with 
Combined Functions 
 
 
 
 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  
This document provides FDAs current thinking on regulation of molecular diagnostic 
instruments that combine in a single instrument both approved/cleared device functions and 
device functions for which approval/clearance is not required.  It also provides advice on the 
type of information that should be provided in a premarket submission for a molecular 
diagnostic instrument that measures or characterizes nucleic acid analytes and has combined 
functions.  In this document, combined functions refers to instruments that serve as a 
component of an FDA-cleared or approved IVD system but can also be configured by the 
user for other test purposes, such as basic research. 
In this document, for simplicity, approved/cleared refers to instruments and functions 
requiring approval through the PMA process or clearance through the 510(k) process.  
Similarly, approval/clearance refers to both the process for approving instruments through 
the PMA process and to the process for clearing instruments through the 510(k) process.    
Approval/clearance is not required refers to instruments or functions that do not need to be 
approved or cleared by FDA, such as those intended solely for use for basic research.  
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.  
  1  Contains Nonbinding Recommendations 
 
 
 
II.  Background 
Molecular diagnostic instruments, for example, real-time thermocyclers, are critical 
components of certain in vitro diagnostic devices (IVDs).  One molecular diagnostic 
instrument is often used to perform multiple unrelated assays, such as those that detect 
methicillin resistant S. aureus (MRSA), Hepatitis C virus, and genetic markers of cystic 
fibrosis.  These types of instruments are not generally approved/cleared alone, i.e., without an 
accompanying assay, because their safety and effectiveness or substantial equivalence cannot 
be evaluated without reference to the assays they run and the assays defined performance 
parameters.  The same instruments may also be used for additional purposes that do not 
require FDA approval or clearance, such as for basic scientific researchpurposes this 
document refers to as functions for which approval/clearance is not required.  In the past, 
FDA has provided informal advice in response to individual inquiries regarding the 
permissibility of having functions for which approval/clearance is not required on an 
instrument intended to be used with approved/cleared in vitro diagnostic assays.  This 
guidance is meant to communicate FDAs policy regarding molecular diagnostic instruments 
with combined functions. 
III.  Scope 
This document applies to molecular diagnostic instruments that are medical devices1 used 
with assays that measure or characterize nucleic acid analytes (human or microbial), and 
that combine both approved/cleared device functions and device functions for which 
approval/clearance is not required in a single instrument.  This document applies to the 
instrument itself (hardware) as well as to any firmware or other software intended to 
operate on or to control the instrument.  This guidance also addresses software that is 
distributed as a stand alone device for use with an approved/cleared molecular diagnostic 
assay. 
The document does not apply to instruments approved/cleared for use with assays that are 
intended to screen donors of blood and blood components and donors of human cells, tissues, 
and cellular and tissue-based products (HCT/Ps) for communicable diseases.  The document 
also does not apply to instruments approved/cleared for blood grouping.  We encourage 
manufacturers wishing to market such instruments with combined functionality to contact the 
appropriate office in the Center for Biologics Evaluation and Research.   
 
 
                                                           
2 See Sections 501 and 502 of the FD&C Act (21 U.S.C. 351 and 352). 
  2  Contains Nonbinding Recommendations 
 
 
The recommendations in this document do not apply to assays and reagents.  FDA has 
separately issued guidance regarding the marketing of Research Use Only (RUO) and 
Investigational Use Only (IUO) assays for clinical use that can be found in the guidance 
entitled Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or 
Investigational Use Only: Frequently Asked Questions found at 
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/uc
m253307.htm. 
IV.  Approval/Clearance of Molecular Diagnostic 
Instruments 
FDA has developed the following policy for premarket submissions for molecular diagnostic 
instruments that have functions for which the sponsor is seeking approval/clearance and 
additional functions for which the sponsor need not seek approval/clearance.  For FDA to 
determine that such submissions meet the regulatory criteria for approval or clearance, as 
applicable, we will assess whether sufficient measures are in place to 1) assure that the 
functions for which approval/clearance is not required do not interfere with or adversely 
affect the safety or effectiveness of the approved/cleared functions, and 2) prevent confusion 
on the part of the end user.  These measures may include implementation of the following: 
  Instrument and software design controls to assure the safety and effectiveness 
of the molecular diagnostic instrument with combined functions. 
  Instrument validation procedures for users to employ following a use for 
which approval/clearance is not required to verify that the use will not 
interfere with subsequent use of the molecular diagnostic instrument as an 
approved/cleared device, and to document that interference did not occur on 
subsequent use. 
  A risk mitigation plan that provides sufficient information to demonstrate that 
any risks that could be introduced by having functions for which 
approval/clearance is not required can be appropriately mitigated. 
  Labeling that clearly distinguishes the approved/cleared functions from 
functions for which approval/clearance is not required (e.g., separate labeling 
for approved/cleared functions and functions for which approval/clearance is 
not required). 
  Result reports that distinguish between the use of the approved/cleared 
functions and the use of the same instrument for functions for which 
approval/clearance is not required (e.g., adding Not approved/cleared by 
FDA in result reports, as applicable). 
Upon review of the information supplied in the premarket submission, FDA will determine if 
such measures described are sufficient to provide a reasonable assurance of safety and 
effectiveness or substantial equivalence for the approved/cleared functionalities.  FDA may 
  3  Contains Nonbinding Recommendations 
 
 
request additional information if we determine that it is necessary to assess safety and 
effectiveness or substantial equivalence of the device. 
FDA will review information regarding functions for which approval/clearance is not 
required only for the purpose of evaluating the risks posed to the approved/cleared functions 
and adequacy of mitigations. We do not intend to review this information with respect to 
performance characteristics or suitability for use, and do not intend to provide comment on 
how instrument functions for which approval/clearance is not required may be marketed, 
described in labeling, or otherwise made available. 
V. Recommendations for Submissions for Molecular 
Diagnostic Instruments with Combined Functions 
1.  New instruments 
For those manufacturers who are developing new molecular diagnostic instruments with  
functions for which approval/clearance is not required, FDA recommends that the software 
for such devices clearly separate the approved/cleared functions from any functions for which 
approval/clearance is not required.  One way to accomplish this separation is a dual boot 
design. When using dual boot design, at start-up the instrument gives a choice of either the 
approved/cleared functions or functions for which approval/clearance is not required, 
requiring the user to choose one or the other depending on the type of assay to be performed.  
The user would not be able to switch between functions without first going back to the start-
up screen.  This approach may serve, for example, to effectively separate the software 
functions and prevent any confusion on the part of the user as to which function the 
instrument is performing and to provide a protective mechanism that prevents the user from 
altering any approved/cleared function parameters. 
Alternative approaches to dual boot designs may be acceptable, provided that non-
interference of approved/cleared functionalities with non-approved/non-cleared 
functionalities is demonstrated by the manufacturer.   
2.  Existing approved/cleared instruments 
a.  For those manufacturers who already have approved or cleared molecular diagnostic 
instruments that are also configured to perform functions for which 
approval/clearance is not required, but have not specifically addressed the issues 
regarding coexistence of approved/cleared functions and those for which 
approval/clearance is not required, FDA intends for you to address the 
recommendations in this document in any new premarket assay submission for which 
the instrument is intended for use. 
  4  Contains Nonbinding Recommendations 
 
 
b.  Alternatively, for manufacturers who would prefer to address these recommendations 
prior to any new premarket assay submission, you should contact FDA to discuss 
potential submissions, and the recommendations outlined in this guidance. 
3.  Submission information, labeling, and marketing 
In determining whether to grant approval/clearance for a molecular diagnostic instrument 
with combined functions for use with an approved/cleared assay, it is FDAs intent to 
consider the following conditions: 
a.  Sponsor demonstrates that functions for which approval/clearance is not required do 
not interfere with approved/cleared functions, by providing sufficient information to 
establish that the approved/cleared functions are not affected by the functions for 
which approval/clearance is not required.  For example, a sponsor may provide or 
describe:  materials and instructions to verify that the use of functions for which 
approval/clearance is not required will not interfere with the approved/cleared 
functions; use of an analyte test panel prior to performing an approved/cleared 
assay; recalibration procedures; instrument cleaning and maintenance, etc.  We 
recommend that the sponsor provide documentation on how the separation of 
approved/cleared functions and those functions for which approval/clearance is not 
required will be managed through system design measures and labeling, and how it 
will be applied to avoid or eliminate user confusion about whether a given assay is 
approved/cleared or not, both during assay operation and reporting of results. 
b.  Sponsor provides a risk/hazard analysis addressing functions for which 
approval/clearance is not required in coexistence with approved/cleared functions, 
and clearly identifies appropriate mitigation measures  Sponsors should consider 
.
human factors in the design of the mitigations such as clear menu options, grayed-out 
software options that are not applicable, etc. 
c.  Sponsor develops separate labeling (including instrument manuals and other labeling) 
for the approved/cleared functions.  Labeling for the approved/cleared functions is 
subject to the requirements for in vitro diagnostic products found in 21 CFR 809.10, 
and should reference only the aspects of the device that were reviewed and 
approved/cleared by FDA.  Additionally, the labeling for the approved/cleared device 
should indicate that the instrument was approved/cleared to run only the 
approved/cleared assays.  This information should be included in decision summaries, 
substantial equivalence and approval letters, and instrument manuals. 
d.  Consistent with the Federal Food, Drug, and Cosmetic Act, the instrument 
manufacturer or sponsor may not adulterate or misbrand the device by promoting non-
approved/non-cleared assays/reagents as approved/cleared for use on the molecular 
  5  Contains Nonbinding Recommendations 
 
 
diagnostic instrument, or otherwise imply, directly or indirectly, that FDA has 
approved/cleared functions for which approval/clearance is not required.2 
 
4.  Promotion and labeling issues  
  
The following provides guidance on labeling and promotion of molecular diagnostic 
instruments with combined functions.  The sponsor of such a product may generally: 
  Promote the instrument as approved/cleared for use with assays that are 
approved/cleared for use on that instrument system. 
  Promote the instrument for uses for which approval/clearance is not required (i.e., 
other than in approved/cleared labeling) without claiming or implying that the uses 
are approved/cleared. 
  Provide information about functions of the molecular diagnostic instrument for which 
approval/clearance is not required separately from instrument labeling provided for 
the approved/cleared product. 
With regard to these products, a sponsor generally should not: 
  Combine approved/cleared and other labeling claims (e.g., you can use this 
instrument for detecting MRSA and for basic research). 
  Combine labeling describing the approved/cleared functions (i.e., users manual, 
brochures, etc.) with information about other functions. 
  Claim or imply approved/cleared status for the other functions. 
  Imply or claim that the instrument is approved/cleared for any assay other than those 
the FDA has specifically approved/cleared for use on the instrument. 
5.  Software/hardware changes 
Once a molecular diagnostic instrument with combined functions is approved/cleared, you 
should notify FDA of changes to the device hardware or software that have the potential to 
affect the approved/cleared functions of the instrument as required under 21 CFR 
807.81(a)(3) and 814.39.  This applies to changes to both approved/cleared hardware and 
software functions and hardware and software functions for which approval/clearance was 
not required.  All changes to both approved/cleared functions and those for which 
approval/clearance was not required should be included in the manufacturers IVD change 
control section in the manufacturers quality system.  Manufacturers should consider the 
potential impact to both class II and III assays used on their system and perform appropriate 
risk assessments to determine the need to submit the changes to FDA, based on the 
recommendations stated in the relevant guidance documents listed below: 
                                                           
2See Sections 501 and 502 of the FD&C Act (21 U.S.C. 351 and 352). 
  6  Contains Nonbinding Recommendations 
 
 
  Deciding When to Submit a 510(k) for a Change to an Existing Device found at 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/UCM080243.pdf 
  Modifications to Devices Subject to Premarket Approval (PMA) - The PMA 
Supplement Decision-Making Process found at 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/UCM089360.pdf 
6.  Third Party assay developers 
Assays submitted to FDA by third party assay developers to be run on user-configurable 
molecular diagnostic instruments, such as those described in this guidance, will be 
reviewed by FDA on a case-by-case basis to determine whether risks are adequately 
mitigated, as described above, for use on molecular diagnostic instruments with 
combined functions.  At a minimum, third party assay developers should provide 
complete instructions for use to allow the end user to perform the assay (including 
procedures to assure non-interference and proper operation of the instrument and software 
for approved/cleared functions) on the specified instrument.  In addition, the labeling 
should not rely on or refer to an instrument user manual that is not part of an 
approved/cleared products labeling. 
VI.  MDR Reporting 
Manufacturers and user facilities are required to report all device-related adverse events in 
accordance with the requirements under 21 CFR 803.10.  Even though molecular diagnostic 
instruments covered by this guidance include  molecular diagnostic device functions for 
which approval/clearance is not required, FDA expects malfunctions, injuries, and deaths 
associated with such functions to be reported as adverse events under 21 CFR Part 803.  All 
instrument device functions, whether approved/cleared or not required to be approved/cleared 
can have a direct or indirect adverse impact on approved/cleared indications.  For third-party 
developed assays, instrument manufacturers and assay manufacturers should be prepared to 
conduct coordinated investigations to determine the root cause of adverse events if 
circumstances so direct. 
  7