Guidance for Industry: 
New Contrast Imaging 
Indication Considerations for 
Devices and Approved Drug 
and Biological Products 
 
Additional copies are available from: 
Office of Combination Products, HFG-3 
Office of the Commissioner  
Food and Drug Administration 
15800 Crabbs Branch Way 
Rockville, MD  20855 
(Tel) 301-427-1934 
(Fax) 301-427-1935 
 http://www.fda.gov/oc/combination 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Combination Products (OCP) in Office of the Commissioner 
Center for Devices and Radiological Health (CDRH) 
Center for Drug Evaluation and Research (CDER) 
 
December 2009 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION.............................................................................................................3 
II.    SCOPE...............................................................................................................................4 
III.  TERMINOLOGY.............................................................................................................4 
IV.  BACKGROUND...............................................................................................................5 
V.  GENERAL PRINCIPLES...............................................................................................6 
VI.  WHAT TYPE OF MARKETING SUBMISSION TO PROVIDE.............................10 
VII.  ILLUSTRATIONS FOR WHEN A DEVICE SUBMISSION (510(K) OR PMA) IS 
SUFFICIENT AND AN NDA SUBMISSION IS NOT NECESSARY......................12 
VIII.  ILLUSTRATIONS FOR WHEN BOTH A DEVICE SUBMISSION AND AN NDA 
SUBMISSION MAY BE NECESSARY FOR A DEVICE MODIFICATION.........14 
IX.  CONSIDERATIONS FOR HOLDERS OF IMAGING DRUG APPLICATIONS..17 
X.    PREMARKET DEVELOPMENT CONSIDERATIONS...........................................18 
XI.    POSTMARKET CONSIDERATIONS.........................................................................20 
XII.  INTERACTION WITH FDA AND THE REVIEW PROCESS................................20 
XIII.  HOW MAY I OBTAIN MORE INFORMATION?....................................................22 
APPENDIX 1 -  MEDICAL IMAGING PRODUCT LABELING CONVENTIONS..........23 
APPENDIX 2  TYPE OF MEDICAL IMAGING PRODUCTS..........................................24 
  2  
1
Guidance for Industry  
New Contrast Imaging Indication Considerations for  
Devices and Approved Drug and Biological Products  
 
 
 
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 intends this guidance to assist developers2 of medical imaging devices and imaging 
drug/biological products (hereinafter more generally referred to as drugs or drug 
products) that provide image contrast enhancement in determining: 
 
  When the imaging device developer may add certain new imaging contrast 
indications to its device for use with already approved imaging drugs without a 
need for a modification of the drug labeling;  
  When the imaging drug developer may add certain new imaging contrast 
indications to its drug for use with already approved imaging devices without a 
need for a modification of the device labeling, and 
  What type of marketing submission(s) 3 the imaging drug or imaging device 
developer should submit to FDA to request approval/clearance to add a new 
imaging contrast indication.  
 
FDA intends for the principles in this guidance to promote timely and effective premarket 
review of, and to promote consistent, appropriate regulation and labeling for imaging 
drugs and devices.  These principles are intended to: 1) promote consistency in the type 
of scientific or technical information submitted to establish a new imaging contrast 
indication for use regardless of the type of marketing submission, and 2) to promote 
compatibility in labeling indication statements. 
 
                                                 
1 This guidance has been prepared by Office of Combination Products, in the Office of the Commissioner, 
in conjunction with the Center for Devices and Radiological Health and the Center for Drug Evaluation and 
Research.   
2 For purposes of this document, the term developer includes manufacturers, sponsors, and other holders of 
marketing applications for medical imaging device, drug, or biological products. 
3 For purposes of this document, the term submission and application are used interchangeably and apply to 
drug, device, and biological product marketing applications or premarket notifications.  Contains Nonbinding Recommendations 
This document supplements existing guidance referred to later in this document 
developed by the Center for Devices and Radiological Health (CDRH), the Center for 
Drug Evaluation and Research (CDER), and the Center for Biological Evaluation and 
Research (CBER), and the Office of Combination Products (OCP). 
 
This guidance does not address the specific scientific or technical content to provide in a 
regulatory submission to demonstrate safety and effectiveness or substantial equivalence 
of an imaging product(s) for specific indications.   
 
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.    SCOPE 
 
 
As part of the Medical Device User Fee Amendments of 2007 (MDUFA) Commitment 
for the Performance Goals and Procedures, in the September 27, 2007 Agreement letter,4 
FDA agreed to develop guidance for medical imaging devices used with contrast agents 
or radiopharmaceuticals.  Specifically, item I.N of the commitment letter states the 
FDA will, after consultation with affected parties, develop a guidance document 
intended to ensure timely and effective review of, and consistent and appropriate 
postmarket regulation and labeling recommendations for, diagnostic imaging devices 
used with imaging contrast agents and/or radiopharmaceuticals approved for the same 
or different indications.  Draft guidance will be published by the end of FY 2008, and will 
be subject to a 90-day comment period.  FDA will issue a final guidance within one year 
of the close of the public comment period.  Draft guidance was published on September 
30, 2008; the comment period closed on January 5, 2009.  FDA held meetings with 
imaging industry stakeholders in July 2008 and August 2009.  This document fulfills 
FDAs commitment to issue the final guidance called for by the commitment letter. 
 
 
III.  TERMINOLOGY 
 
 
For purposes of this document, the following conventions apply. 
 
  Imaging drug: Imaging drugs are drugs and biological products (including 
radiopharmaceuticals) intended for use in medical imaging.  This description is 
generally consistent with the term contrast agent. 
 
                                                 
4 http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Overview/Medical 
DeviceUserFeeandModernizationActMDUFMA/UCM109102.pdf 
  4 Contains Nonbinding Recommendations 
  Indication statement: Indication statement, for the purposes of this document, is 
synonymous with the definition of Indication and Usage under 21 CFR 201.57 
and the definition of Indications for Use under 21 CFR 814.20(b)(3)(i).5  The 
approved indication is included in the FDA approval letters and accompanying 
labeling for NDAs, BLAs, and PMAs.6  The indication is stated in the Indication 
for Use Statement form that accompanies the premarket notification 510(k) 
clearance letter.  FDA expects that other sections of the labeling would clarify but  
not expand the use beyond the indication statement.7 
 
  Imaging contrast indication: Imaging contrast indication is a statement in the 
indication section of the imaging drug labeling that describes the use of the drug.  
Generally, when an imaging drug is intended to be used with a specific imaging 
device, the imaging contrast indication also appears in the device labeling. 
 
Existing FDA guidance identifies imaging drug contrast indications in four broad 
indication areas.8  For additional information see section VI.B Considerations for 
When an NDA is Appropriate.   
 
 
IV.  BACKGROUND 
 
 
Medical imaging is a rapidly developing area with the potential to provide novel 
diagnostic information to guide patient management or to facilitate image guided direct 
delivery of diagnostic or therapeutic products to previously inaccessible areas of the 
body.  Medical imaging technologies are also important for several critical path 
methodologies (e.g., biomarkers, surrogate markers, and personalized medical decision 
making).   
 
Most medical imaging depends solely on the device technology to produce and display 
images; e.g., ultrasound (US), computerized tomography (CT), magnetic resonance 
imaging (MRI), and traditional radiology (x-ray) techniques.  However, imaging drugs 
are sometimes used in conjunction with these imaging devices to provide image 
                                                 
5 21 CFR 201.57 (c)(2) Indications and usage. This [labeling] section must state that the drug is indicated 
for the treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition, or of a 
manifestation of a recognized disease or condition, or for the relief of symptoms associated with a 
recognized disease or condition.  21 CFR 814.20(b)(3)(i) Indications for Use A general description of the 
disease or condition the device will diagnose, treat, prevent, cure, or mitigate, including a description of the 
patient population for which the device is intended. 
6 NDA (new drug application), BLA (biologics license application), PMA (premarket approval 
application).  For purposes of this document references to an NDA includes BLA submissions. 
7 For purposes of this document, the indication statement is distinct from the sponsors intended use 
summary provided in a 510(k) notification under 21 CFR 807.92(a)(5).  
8 FDA Guidance for Industry, Developing Medical Imaging Drug and Biological Products: Part 2, Clinical 
Indications;  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071603.
pdf 
 
  5 Contains Nonbinding Recommendations 
enhancement.  For example, for CT and MRI, the addition of an imaging drug may 
improve the visualization of tissues, organs, and physiologic processes in part by 
increasing the relative difference of imaging signal intensities in adjacent regions of the 
body.  
 
For other imaging technologies such as radiopharmaceutical imaging (SPECT or PET),9 
the device alone cannot produce a usable image.  Therefore, in order to produce and 
display a usable image, it is necessary to administer an imaging drug to the patient before 
using the imaging device.  For additional background on the types of imaging products, 
see Appendix 2. 
 
Although intended to be used together, technological advancements with imaging devices 
and imaging drugs generally may not proceed at the same rate.  Historically, imaging 
device software and hardware engineering technologies that utilize imaging drugs evolve 
rapidly (i.e., changes occur once or twice a year) and typically out-pace development of 
new imaging drugs or new indications for already approved imaging drugs.  Device 
advancements may create an opportunity for a new indication using an approved imaging 
drug without necessitating a change to the imaging drugs labeling; i.e. dose, rate, or 
route of administration.  For example, if a drug that is approved for use in imaging the 
lung is systemically distributed in the body, new device software might allow the 
identical drug to produce an image of the liver.  However, if the drug and device 
manufacturer do not cooperate to seek approval to add the new liver imaging indication 
in the drug labeling, the pathway to market the new indication using the new device 
technology alone is often unclear.  The purpose of this guidance is to describe the 
principles and provide examples under which drug or device developers can seek 
marketing approval/clearance to add new imaging contrast indications to the medical 
device using an already approved imaging drug. 
 
In developing these principles, FDA considered the scientific and technical issues that 
may occur when using imaging drugs and devices together, approaches to leverage prior 
Agency decisions, approaches to ensure consistency of information regardless of the type 
of submission being used to establish new imaging contrast indications, and approaches 
to ensure the consistency of the regulatory vehicle for submission under the drug, 
biological product, or device provisions being used to establish similar types of imaging 
contrast indications.  
 
 
V.  GENERAL PRINCIPLES  
 
 
To ensure the safe and effective use of both imaging drugs and imaging devices, FDA 
believes that, the imaging drug and imaging device labeling should be generally 
consistent.  Within this context, however, under appropriate circumstances as described 
in this document, the labeling of the imaging device alone may be able to provide 
                                                 
9 SPECT stands for single photon emission computerized tomography; PET stands for positron emission 
computerized tomography. 
  6 Contains Nonbinding Recommendations 
sufficient information about a new imaging contrast indication when using an imaging 
drug in accordance with its approved drug labeling.  This instance may occur when the 
device technology does not change the drug characteristics and when the drug use is 
otherwise consistent with its approved imaging drug labeling.10  In other instances the 
imaging drug labeling may be able to provide sufficient information about a new imaging 
contrast indication using an imaging device in accordance with its approved device 
labeling.  In determining consistency with approved labeling, FDAs considerations 
include, for example, labeling for the indication statement, dosing regimen (dose, rate, 
route of administration), conditions of use, patient population, and safety information.  
The Agency notes that individual imaging contrast indications may present unique or 
complex issues of safety or effectiveness that necessitate a review approach that varies 
from the one set forth below.  Nonetheless, the agency expects to review most premarket 
applications for imaging product indications involving a drug and a device under the 
following approach to determine whether a submission should be provided for the 
imaging device, imaging drug, or for both imaging products. 
 
1.  Imaging device submission:  When a new imaging device or device modification 
enables an approved imaging drug (i.e., at its approved formulation, dose, dosing 
regimen, rate, and route of administration) to be used for a new imaging contrast 
indication in a manner that is consistent with its approved indication, in most 
cases, FDA expects that a device submission from the device application holder 
alone would be sufficient to add the new imaging contrast indication to the 
device.  The device submission would be either an original device application for 
a new device or supplemental device application for a modified device.  Through 
this process, the imaging device developer would add the modified imaging 
contrast indication to the device labeling without the need for a change to the 
imaging drug labeling.  For example, when new device software allows for the 
enhancement of the sensitivity and specificity of the same imaging site already 
identified in the approved imaging drug labeling, and the drug is administered in 
accordance with its approved labeling and the labeling does not need revision to 
ensure safety and effectiveness, the Agency believes in most instances a device 
submission and device labeling change alone should suffice. 
 
2.  Imaging drug submission:  In contrast, when an imaging drug modification (i.e., 
formulation, dosage, rate, or route of administration) enables the currently 
approved/cleared imaging device to be used for a new indication for use without a 
change to the device, the NDA/BLA holder should submit a supplement to FDA 
to request approval for such a change.  For example, an NDA submission would 
be most appropriate for a drug reformulation that allows enhanced biodistribution 
to a new area, but uses the same imaging software.  In most instances, FDA 
expects a submission of an NDA submission to be sufficient to add such an 
indication to the drug labeling without the need for a submission of a device 
application or a labeling change to the imaging device.   
                                                 
10 Examples of imaging device - drug interactions that may affect the characteristics of the imaging drug 
include ultrasound rupture of microbubbles and light activation of molecules to release a singlet oxygen 
species.  The safety and efficacy of these changes may vary depending on the different tissues being 
imaged. 
  7 Contains Nonbinding Recommendations 
3.   Imaging device and imaging drug submissions:  In some instances, however, the 
device modification required to support the new imaging contrast indication may 
cause the drug and device to interact in a manner that affects the safety or 
effectiveness of the product(s), may change the imaging dosing, safety or 
effectiveness information, or may produce labeling inconsistencies.  In such 
circumstances, FDA expects that both the drug and device labels would need to be 
revised to ensure the safe and effective use of both products for the new imaging 
contrast indication.  If this is the case, the following principles would apply: 
 
  When a new device or an imaging device modification necessitates a change 
in the imaging drug formulation, dosage, rate, or route of administration of the 
currently approved imaging indication, or when the new or modified device is 
for a new indication not in the approved drug labeling, FDA will generally 
expect a submission from the holders of both the drug and device applications 
to ensure labeling conformity.  For example, if a change in device design 
provides for enhanced imaging at lower doses of the drug, FDA may 
determine the new drug dosing information should be included in both the 
imaging drug and device labels in order to help ensure that the drug will be 
used safely and effectively;  
 
  When an imaging drug modification (i.e., formulation, dosage, rate, or route 
of administration) necessitates a change in the approved imaging device 
performance characteristics, specifications, or design for its currently 
approved/cleared imaging indication or for a new indication for use, FDA will 
generally expect a submission of both a drug and a device application to add 
the new indication and to ensure labeling consistency.  For example, an NDA 
supplement would be appropriate for a change in an ultrasound drug 
formulation to enhance drug stability for an existing indication; and a device 
submission would be appropriate for a corresponding change in the ultrasound 
device design to image the reformulated drug. 
 
Regardless of which label (imaging device or imaging drug or both) adds the new 
imaging contrast indication, the safety and effectiveness of the new indication should be 
established by data collected from appropriately designed clinical trials using both the 
imaging drug and the imaging device.  In general, FDA expects that the regulatory 
approval pathway (e.g., 510(k), PDP, PMA, PMA supplement, NDA, NDA efficacy 
supplement, NDA 505(b)(2), or NDA labeling supplement) should not affect the 
scientific and technical information that is most appropriate for establishing the safety 
and effectiveness of the new imaging contrast indication.  (For additional information see 
Section IX, Premarket Development Considerations.)  Further, the labeling of product(s) 
that adds the new indication statement should reflect the essential information that 
establish the imaging contrast indication; e.g., the clinical study description, imaging 
device characteristics and settings, imaging drug dosing regimen, target organ.  By 
developing labeling that relies on consistent types of information, FDA intends to 
minimize the potential for misleading information across the imaging drug and device 
labels for similar indications.   
 
  8 Contains Nonbinding Recommendations 
A.  Determination of Lead Center Responsible for Premarket Review 
 
Most imaging devices and drugs approved for use with a class of imaging products do not 
meet the definition of a combination product under 21 CFR Part 3; e.g., when an imaging 
device is approved for use with a class of imaging drugs (e.g., gadolinium contrast) or 
when a drug is approved for use with a class of devices (e.g., MRI).11  If an imaging 
device is not a combination product, a manufacturer of an imaging device who intends to 
develop a new imaging contrast indication for use with a class of imaging drugs should 
submit a device application to CDRH for review.  During the review process, CDRH will 
consult with CDER on issues including, but not limited to, the scientific/technical, 
risk/benefit, labeling, potential interaction issues for the drug or drug class.12  Similarly, a 
manufacturer of an imaging drug who intends to develop a new imaging contrast 
indication for use with a class of devices should submit a drug application to CDER for 
review.  CDER will consult with CDRH on all device related issues. 
 
However, in some instances, the use of a certain diagnostic imaging device and imaging 
drug may constitute a combination product under 21 C.F.R. 3.2(e)(3).13  For example, a 
specific imaging drug used to bind receptors for imaging that uses a dedicated software 
algorithm may constitute a combination product.  Although a detailed discussion of how 
FDA applies combination product authorities is beyond the scope of this guidance, if a 
manufacturer has a combination product, the lead center determination will be in 
accordance with the primary mode of action regulatory provisions.14  Manufacturers of a 
specific drug-device imaging product may wish to contact FDA Office of Combination 
Products to discuss whether a request for designation would be useful.15   
 
As described further in Section XI, Interaction with FDA and the Review Process, for the 
developer of an imaging device wishing to add a new imaging contrast indication for a 
class of imaging drugs, the supportive clinical trial(s) should be conducted under the 
Investigational Device Exemption regulations at 21 CFR 812 with a submission to 
CDRH.  Similarly, for the developer of an imaging drug wishing to add new imaging 
contrast indications for a class of devices, the supportive clinical trials should proceed 
under the Investigational New Drug regulations at 21 CFR Part 312 with a submission to 
CDER.  For a combination product, the submission should proceed under the lead center 
                                                 
11 Although these class products do not meet the definition of a combination product at 21 CFR 3.2, the use 
of each product is integrally related to the approved indications and the products would be prescribed for 
use with each other.   
12 Imaging drug and biological products including radiopharmaceuticals are regulated in CDER. 
13 21 CFR 3.2(e)(3) A drug, device, or biological product packaged separately that according to its 
investigational plan or proposed labeling is intended for use only with an approved individually specified 
drug, device, or biological product where both are required to achieve the intended use, indication, or effect 
and where upon approval of the proposed product the labeling of the approved product would need to be 
changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or 
significant change in dose. 
14 Final rule for Definition of the Primary Mode of Action of a Combination Product, published August 25, 
2005, Federal Register, http://edocket.access.gpo.gov/2005/pdf/05-16527.pdf,  See 21 CFR 3.4. 
15 FDA guidance How to write a request for designation;  
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126053.htm 
 
  9 Contains Nonbinding Recommendations 
as determined by the product specific primary mode of action and typically the 
investigational application would be of the type administered by the lead center. 
 
 
VI.  WHAT TYPE OF MARKETING SUBMISSION TO PROVIDE 
 
 
Under the concepts set forth in Section V General Principles, FDA believes certain new 
imaging contrast indications that are consistent with imaging drug labeling can be 
reviewed in a device submission alone when they entail only device modifications and 
when a change in the approved drug labeling would not be necessary.  In other 
circumstances both a device and drug marketing submission may be necessary.16  
Therefore, when a device sponsor considers what type of submission(s) may be 
appropriate for their device change, there are two issues to consider: What type of device 
application should be submitted and when would a drug submission be appropriate?  To 
assist in determining the type of device application to submit, CDRH previously issued 
two guidance documents that may be useful in determining the type of device application 
to submit when adding a new contrast imaging indication: a) Guidance for Industry: 
General/Specific Intended Use (1998) and b) Deciding When to Submit a 510(k) for a 
Change to an Existing Device (1997).  While neither is intended to apply to drug products 
or combination products, these guidance documents do provide starting point principles 
for determining whether a 510(k) or PMA is most appropriate.17  The following section 
VI.A applies these concepts to imaging devices.  Section VI.B provides considerations 
for when a NDA is appropriate.  Section VII and VIII provide further illustrations on the 
types of marketing submissions. 
 
A.  Considerations for the type of device submission: 510(k) or PMA 
 
In determining whether a new device or a modified device is appropriate for review and 
clearance under a 510(k), FDA intends to assess whether the proposed device can be 
deemed substantially equivalent to a predicate device in accordance with 21 CFR 
807.100(b), which states the following.  
 
(1) The device has the same intended use as the predicate device; and 
  (2) The device:  
(i) Has the same technological characteristics as the predicate device; or 
(ii)(A) Has different technological characteristics, such as a significant change 
in the materials, design, energy source, or other features of the device 
from those of the predicate device; 
                                                 
16 OCP is currently developing a guidance document for public review and comment that will address the 
factors FDA expects to consider in determining whether a single or multiple marketing applications should 
be submitted for a combination product. 
17 FDAs guidance on Deciding When to submit a 510(k) for a Change to an Existing Device states in the 
Scope section that the guidance is not intended to apply, although it may, to combination products, such 
as drug/device or biologic/device combinations.  FDAs Guidance for Industry: General/Specific Intended 
Use (1998) provides information on medical devices for purposes of determining substantial equivalence.  
It does not provide details on combination products under device applications or changes to add a drug use. 
 10 Contains Nonbinding Recommendations 
(B) The data submitted establishes that the device is substantially 
equivalent to the predicate device and contains information, including 
clinical data if deemed necessary by the Commissioner, that demonstrates 
that the device is as safe and as effective as a legally marketed device; and 
(C) Does not raise different questions of safety and effectiveness than the 
predicate device. 
 
Typically, FDA receives 510(k) submissions for: 1) adding the use of an approved 
imaging drug to the labeling of a 510(k) device that is cleared for use without an imaging 
drug, or 2) for using a new or modified device with an approved imaging drug for a new 
imaging contrast indication not provided in the drug labeling. 
 
FDAs first step in determining the appropriate type of device submission is to assess 
whether the sponsors selected predicate device is appropriate.  If the proposed device has 
a different intended use from the intended use identified in the cleared predicate device, 
the proposed device will receive a not substantially equivalent (NSE) determination 
based on a new intended use, and, therefore, will be reviewed under a PMA or De Novo 
application. 
 
Once an appropriate predicate device is considered acceptable by FDA, the decision on 
whether the proposed device may be substantially equivalent to the predicate device 
depends on the evaluation of the technologic characteristics and the evaluation of safety 
and effectiveness questions as illustrated in the CDRH 510(k) decision tree.18  FDA notes 
that since the imaging drug is part of the device indication, these questions should include 
questions related to the imaging drug.  After the review is completed, if the proposed 
device is considered NSE to the predicate device due to questions of safety and 
effectiveness, the sponsor will be advised to submit a PMA or De Novo application.   
 
After a determination about what type of device submission is appropriate, the developer 
should consider whether its proposed indication would be a new indication for the 
imaging drug or would create a labeling inconsistency for the drug.  If so, then an NDA 
should be submitted along with the device application.   
 
B.  Considerations for When an NDA is appropriate. 
 
Imaging drug indication differences are based on whether the indication is within the 
original imaging categories identified in Section V, General Principles and whether the 
conditions of use are the same.  A determination of when an NDA submission should be 
provided depends on the consistency with the labeled indication and on the safety or 
effectiveness information (e.g., patient population, dose, dosing regimen, frequency of 
repeat studies, concomitant medication, and risk factors).  Imaging drug indications do 
not expressly address the concept of general vs. specific indications as referenced above 
for determining the type of device submission; instead imaging drug indications are 
categorized as: 1) Structural delineation, 2) Disease or pathology detection or assessment, 
                                                 
18 Additional information is available under 510(k) Memorandum K-86-3 issued June 30, 1986; 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm081383.htm 
 11 Contains Nonbinding Recommendations 
3) Functional, physiological or biochemical assessment, or 4) Diagnostic or patient 
management.19  As explained in the guidance document referenced below, any change 
from one category to another is considered a new indication.  Device changes that would 
generally be inconsistent with an existing drug label and for which an NDA submission 
would be appropriate include changes such as the following: 
 
  Change in drug imaging indication category (change from structural to disease 
or pathology detection), 
  Change in patient population, 
  Change in dose, rate, route, or dosing regimen, 
  Change in safety profile, or 
  Change in the device labeling that could introduce confusing or misleading 
information for healthcare providers when relying on the imaging device,  
imaging drug or both labels. 
 
Therefore, the initial step in determining whether a device proposed change is consistent 
with the drug labeling is to carefully consider the approved indication of the drug.  The 
appropriate type of submission may be an NDA efficacy or labeling supplement. (For 
additional information see Section IX, Considerations for Holders of Imaging Drug 
Applications.) 
 
 
VII.  ILLUSTRATIONS FOR WHEN A DEVICE SUBMISSION (510(K) 
OR PMA) IS SUFFICIENT AND AN NDA SUBMISSION IS NOT 
NECESSARY 
 
 
As provided by the examples below, there are circumstances where the device proposed 
change is consistent with the existing drug indication and can be reviewed under a 
510(k)/PMA alone.  In such an instance, a submission of an NDA supplement to change 
the drug label would not be necessary before approving or clearing the device.   
 
Scenario: Both the imaging device and one specific imaging drug (gadolinium) are 
cleared and approved, respectively, for contrast magnetic resonance angiography (MRA) 
of the aortoilliac region.  The device developer submits a new 510(k) requesting 
clearance for its device modified by adding quantitative measurement to its existing 
software to increase the sensitivity/specificity detecting aortoilliac lesions with of 95% 
stenosis using the approved imaging drug.  The approved imaging drug labels clinical 
trials section identifies the primary endpoint as a visual comparison of pre and post 
contrast images detecting lesions with > 50% stenosis. 
 
 
                                                 
19 FDA Guidance for Industry, Developing Medical Imaging Drug and Biological Products: Part 2, 
Clinical Indications;  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071603.
pdf 
 12 Contains Nonbinding Recommendations 
1.  Is 510(k) or PMA appropriate? 
 
For purposes of this scenario, the sponsors cleared MRA device for use with the 
approved aortoilliac imaging drug would be an acceptable predicate for the 
increased sensitivity and specificity of the lesion detection.  However, the use of 
the MR device and specific gadolinium imaging drug to add specific 
quantification of aortoilliac lesions at 95% stenosis may raise different questions 
of safety and effectiveness (e.g., the validation of the sensitivity and specificity of 
a quantitative measure as compared to a visual display of qualitative data that 
would be subject to clinical interpretation).  As such, the 510(k) may be found to 
be NSE. 
 
2.  Is an NDA supplement appropriate? 
 
No, an NDA supplement would not be necessary.  The gadolinium imaging drug 
is approved to evaluate aortoilliac occlusive disease in adults with known or 
suspected peripheral vascular disease.  The approved labeling clinical trials 
section identifies the primary endpoint as a visual comparison of pre and post 
contrast images in order to detect lesions with > 50% stenosis.  The device 
software increases the sensitivity/specificity of the visual detection or adds a 
computer assisted component to aid the detection to lesions that would be within 
the aortoilliac MRA imaging drugs indication.  Therefore, the device 
modification would be consistent with the approved indication of the approved 
imaging drug.    
 
The following additional examples further illustrate other device proposed labeling 
changes (regardless of device submission type) that are considered within the imaging 
drug indication and for which an NDA submission would not be necessary.  
 
a.  Imaging drug for Ultrasound (US): 
  
An approved imaging drug (ultrasound microbubble) is indicated for 
structural delineation of the left ventricular endocardial border in patients with 
suboptimal non-contrast echocardiography.  Assume that the device design is 
changed to add gating to increase the sensitivity and specificity of the LVO 
(left ventricular opacification) and border detection.  The device change does 
not alter the approved drug indication; and therefore, an NDA supplement is 
not necessary.  However, if the gating was to measure left ventricular ejection 
fraction, this use would not be consistent with the approved drugs indication. 
 
b.  Imaging drug for Computerized Tomography (CT):   
 
Most imaging iodinated contrast drugs are indicated for CECT (contrast 
enhanced) imaging of the head and body, excretory urography, and peripheral 
venography.  CT scans have evolved to Multidector CT scanners.  The 
addition of imaging iodinated contrast drug enhancement to the device 
 13 Contains Nonbinding Recommendations 
labeling using Multidector CT within same areas and dosing as approved in 
CECT would be considered within the approved imaging drugs indication.20 
 
c.   Imaging Drug for MR  Body Indication:   
 
According to the currently approved labeling, MR imaging gadolinium drugs 
with a body indication are considered as limited to the intrathoracic 
(excluding the heart), intraabdominal, and retroperitoneal regions.  Device 
MR modifications for gadolinium enhancement to increase structural 
identification of masses within these regions (but not within specific organs) 
are considered to be within the approved drug imaging indication. 
 
 
VIII.  ILLUSTRATIONS FOR WHEN BOTH A DEVICE SUBMISSION 
AND AN NDA SUBMISSION MAY BE NECESSARY FOR A 
DEVICE MODIFICATION 
 
 
As provided by the examples below, there are circumstances where the device proposed 
labeling change is inconsistent with the existing drugs indication and cannot be reviewed 
under a 510(k)/PMA alone.  Therefore, a submission and approval of an NDA 
supplement to change the drug label would be necessary before or concurrent with 
approval or clearance of the device.   
 
Scenario 1 - Ultrasound Contrast (US): The device is cleared for general US non-
contrast imaging in several areas of the body and for contrast enhanced 
echocardiography using FDA approved US imaging drugs in accordance with their 
labeling.  The imaging drug (microbubble) is approved for use in patients with 
suboptimal echocardiograms to opacify the left ventricular chamber and to improve 
the delineation of the left ventricular endocardial border.  The device has been 
modified and the sponsor submitted a 510(k) requesting clearance to add the use of 
the US imaging drug: 1) for the identification of myocardial perfusion defects, 2) for 
imaging low flow/smaller vessels in abdomen and peripheral vascular disease for the 
detection and assessment of aneurysms, plaque, and intimal thickness, and 3) to 
qualitatively assess tumors, monitor growth, vascularization & treatment 
effectiveness. 
 
1.  Is a 510(k) or PMA appropriate? 
 
For the purposes of this scenario, the sponsor selected its own cleared US 
device as the predicate.  FDA expects that the US device will have different 
technological characteristics when using the US imaging device and 
microbubble in different areas of the body (e.g., the wash-in/wash-out 
techniques to improve delineation of the LV border vs. rupture the 
microbubble for identification of the myocardial perfusion defects vs. 
                                                 
20 FDA notes that imaging iodinated contrast drug labels do not specify the use of Multidector CT. 
 14 Contains Nonbinding Recommendations 
evaluation of peripheral vessels or aneurysms).  These technological 
differences raise different safety and effectiveness questions as compared to 
the predicate device which include: interactions of the device megahertz 
energy that may rupture the microbubbles that may lead to adverse events, 
new clinical endpoints, new patient populations, and different benefits/risks 
ratio analysis.  Also, the use of the US imaging drug for myocardial perfusion 
defects is a change from a cardiac general structural identification to a 
disease/pathology detection indication.  The use in other areas of the body, 
and the use for aneurysms or intimal plaque measurements are substantially 
different indications with patient management implications.  The quantitative 
assessment of tumor growth would raise different questions of safety and 
effectiveness for the new imaging endpoint correlation with disease outcomes.  
For these reasons, the 510(k) would be considered NSE. 
 
2.  Is an NDA supplement appropriate? 
 
Yes, an NDA supplement would be appropriate because each of these 
proposed indications is different from the existing imaging drug indication as 
follows. 
 
a. The US imaging drug is not approved for evaluation of cardiac/ myocardial 
perfusion.  The existing US imaging drug indication is for the opacification of 
the left ventricle and visualization of the LV endocardial border (structural).  
A new use for myocardial perfusion imaging in patients with suspected or 
known coronary artery disease would represent a new functional or diagnostic 
indication even though it is in the same organ.  New efficacy data would be 
needed to document image findings.  New safety data would be needed using 
the different US wash-in/wash-out techniques and ultrasound mechanical index 
values to evaluate possible microsphere cavitations or rupture with associated 
arrhythmias.   
 
b. As above, the existing US imaging drug indication does not include an 
evaluation of a vessel.  Overall, the new evaluation of vascular structures,  
aneurysm, plaque or intimal thickness raises new safety and effectiveness 
(risk/benefit) questions related to demonstration that contrast US meaningfully 
enhances structure delineation disease/pathology detection or patient 
management (depending upon the endpoints) compared to non-contrast US.  
The clinical utility of certain endpoints (e.g. measurements of change in 
plaque or intimal thickness) would need verification.  As such, this use would 
be considered as a new specific indication and not similar to the existing US 
imaging drugs indication.  
 
c. Also, similar to the other indications in this scenario, the proposed use of 
the US imaging drug to qualitatively assess tumors, monitor growth, 
vascularization and treatment effectiveness is not part of the existing US LV 
endocardial border indication.  This use would be a change from a structural 
to a functional, disease/pathology detection indication or a patient 
 15 Contains Nonbinding Recommendations 
management indication (depending upon the endpoints).  These proposed uses 
would all be new indications for which safety and effectiveness verification 
would be needed.  An NDA supplement should be provided to establish the 
new indications and associated revisions to the imaging drugs labeling. 
 
Scenario 2 - MR Contrast Breast imaging: The MR device is cleared for non-
contrast breast imaging in patients with abnormal mammograms or non-palpable 
breast lesions.  The device developer would like to submit a 510(k) requesting 
clearance for use of gadolinium imaging drugs to enhance breast imaging in the same 
patient population.  At the time of submission, an FDA approved gadolinium imaging 
drug labeled for breast MR imaging does not exist. 
 
1.  Is a 510(k) or PMA appropriate? 
 
For the purposes of this scenario, the sponsor selected its own cleared device 
as the predicate.  Since the predicate device was cleared with the same 
indication as the proposed device, but without the use of the gadolinium 
imaging drug, it would be considered an acceptable predicate for a 510(k) 
submission.  However, the 510(k) submission for the imaging device for use 
with the imaging drug could not be found substantially equivalent to the 
predicate until an imaging drug was concurrently approved for breast imaging.  
 
2.  Is an NDA supplement appropriate? 
 
Yes, to date FDA has not approved a gadolinium imaging drug for breast 
contrast enhancement.21  Based on current practice standards, this use would 
likely be a change from structural imaging to a disease or pathology detection 
imaging drug indication.  There would be new safety and effectiveness issues 
for this new indication.  An NDA efficacy supplement would be expected. 
 
Scenario 3 - Qualitative to Quantitative Imaging:  The device is cleared for MR 
contrast imaging for qualitative structural identification of lesions in several areas of 
the body including the liver.  An MR gadolinium imaging drug is approved for 
qualitative dynamic and hepatic phase imaging of focal liver lesions during a single 
imaging session.  The device modification is to add software enhancements to add 
dynamic MR imaging of the liver to quantitatively assessment of tumors to monitor 
growth, vascularization, and treatment effectiveness.  
 
1.  Is a 510(k) or PMA appropriate? 
 
For this scenario, the sponsor identified its cleared device as the predicate.  
However, the technological enhancements to add quantitative imaging are 
different from the original design and, as such, raise different questions of safety 
                                                 
21 Based on currently labeled gadolinium imaging drugs, the body indication statement is limited to the 
intrathoracic (excluding the heart), intraabdominal, and retroperitoneal regions.  In this indication, specific 
organs are not part of the indication.  Also, the breast is extrathoracic.   
 
 16 Contains Nonbinding Recommendations 
and effectiveness for treatment response (e.g., the validation of the sensitivity and 
specificity of discrete quantitative measures of drug uptake to product specific 
diagnostic information such as lesion density, pattern, and configuration).  For 
this reason, the 510(k) may be considered NSE.   
2.  Is an NDA supplement appropriate? 
 
Yes, for the imaging drug (gadolinium) already approved for liver MR imaging, 
an NDA supplement should be submitted for the new indication.  The approved 
MR gadolinium imaging drug is for T1-weighted magnetic resonance imaging 
(MRI) of the liver to detect and characterize lesions in adults with known or 
suspected focal liver disease.  This indication is a mixed structural and pathology 
detection characterization (e.g., hepatocellular carcinoma, cholangiocarcinoma, 
metastasis, focal lymphoma, presence or absence of a lesion).  However, the 
specific quantitation of tumors to monitor growth, vascularization & treatment 
effectiveness is a patient management indication that is not part of the approved 
imaging drugs indication.  Presumably, the dynamic image involves kinetic 
measures and new end points that are used to make pathology/disease evaluations 
that would be considered as a new indication.  An NDA efficacy supplement 
should be submitted to achieve imaging drug labeling for the new indication. 
 
In all of the above scenarios, when the 510(k) is found to be NSE (not substantially 
equivalent) to a predicate, the submission should be a PMA.  If the submitter would like 
FDA to consider a DeNovo petition, FDA recommends having a detailed discussion that 
includes consideration of what type of Special Controls Guidance could be developed to 
mitigate the risks of the device. 
 
 
IX.  CONSIDERATIONS FOR HOLDERS OF IMAGING DRUG 
APPLICATIONS  
 
 
Holders of an NDA or BLA for an imaging drug or biological product who seek to 
develop new contrast indications that refer to information developed in a device 
submission should submit supplements to their NDA/BLA.  In addition, if FDA approves 
or clears a new imaging contrast indication in a device submission (which did not require 
a change to the drug labeling), the NDA/BLA holder may nevertheless submit a labeling 
supplement to add the indication to the imaging drug.  Furthermore,  
 
  If the NDA holder wishes to request exclusivity, then an efficacy supplement 
should be submitted.22   
  When an NDA holder wishes to add clarifications to an imaging drug label and an 
NDA supplement is not otherwise needed, these labeling changes would be 
submitted as a labeling supplement.  
                                                 
22 Under 21 CFR 314.108, FDA may grant drug product exclusivity for studies not conducted or sponsored 
by the applicant.  On a case-by-case basis, FDA will consider whether exclusivity may be appropriate when 
relying on studies submitted in the PMA/510(k).  
 17 Contains Nonbinding Recommendations 
  If the NDA proposes a new indication, new dose, or new dose rate or route, that 
requires new device technology, then in parallel with the NDA efficacy 
supplement, the device sponsor would submit the appropriate device submission 
in accordance with the principles under Section VI, What type of Device 
Marketing Submission to Provide. 
 
 
X.  PREMARKET DEVELOPMENT CONSIDERATIONS 
 
A.  Considerations for Data Necessary to Support Approval of a New Imaging 
Contrast Indication 
 
As noted in Section III. Terminology, there are four large categories of imaging contrast 
indications.  Existing FDA guidance documents provide recommendations on what to 
include in a submission and how to submit device technology information on certain 
devices (ultrasound, MRI, SPECT, PET).23  In other existing FDA guidance documents, 
the Agency also provides detailed recommendations on the data necessary to establish the 
safety and effectiveness of different types of imaging contrast indications associated with 
imaging drug and biological products (Developing Medical Imaging Drug and Biological 
Products, Part I, 1, 2 and 3).24  This set of documents includes information respectively 
on the following:  
  Conducting Safety Assessments;  
  Clinical Indications; and  
  Design, Analysis, and Interpretation of Clinical Studies 
Further, for the subset of imaging products that are combination products, the FDA 
guidance Early Development Considerations for Innovative Combination Products 
provides information on how known information might be useful in product 
development.25   
 
FDA recommends that manufacturers of imaging drug-device combination products or 
manufacturers of imaging devices for use with an imaging drug class consider these 
existing guidance documents as a starting point for development plans for their specific 
                                                 
23 Emission Computed Tomography Devices and Accessories (SPECT and PET) and Nuclear Tomography 
Systems; 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UC
M073797.pdf; Magnetic Resonance Diagnostic Devices; 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm073817.htm 
24 FDA guidance Developing Imaging Drug and Biological Products, Part 1: Conducting Clinical Safety 
Assessment, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071600.
pdf ; Part 2: Clinical Indications; 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071603.
pdf;   Part 3: Design, Analysis and Interpretation of Clinical Studies, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071604.
pdf 
25 Early Development Considerations for Innovative Combination Products; 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126050.htm 
 
 
 18 Contains Nonbinding Recommendations 
imaging contrast indication.  Because of the breadth, innovation and complexity of these 
imaging drug-device systems, there is no single clinical trial design that would be 
appropriate for all products or indications.  However, FDA expects that the scientific and 
technical questions posed by a specific imaging contrast indication, patient population, 
and set of products would be similar regardless of the center lead or type of marketing 
submission being used.  Thus, most new imaging contrast indications should include 
comparable documentation collected from appropriately designed clinical trials of the 
imaging drug-device as well as preclinical test results, and, when appropriate, device 
software or new technology validation.   
 
FDA recognizes that the type and volume of data necessary to submit may vary in 
accordance with such factors as the indication, patient population, safety questions, and 
drug characteristics.  When the dose, dosing regimen, rate and route of administration of 
the imaging drug is the same and the device does not interact with the drug, it is likely 
that FDA guidance Developing Imaging Drug and Biological Products Part 3: Design, 
Analysis and Interpretation of Clinical Studies will be the most relevant guidance.  
Further, in some instances the type of trial design may be tailored to focus on certain 
issues; e.g., electrophysiologic studies to evaluate effect of microbubble rupture on 
ventricular arrhythmia.  Also, as appropriate, in some instances published literature or 
other public documents may be able to provide the information to establish an indication.   
 
1.  Imaging Drug Class Considerations 
 
When an imaging device manufacturer is considering a new imaging contrast 
indication for a broad class of imaging drugs (e.g., gadolinium), in developing the 
clinical trial designs, the manufacturer should consider what is common and what 
is unique about the class of drugs.  For example, each class of imaging drugs 
described in Section IV. Background (e.g., microbubbles, paramagnetic metallic 
ions linked to different chemicals, iodinated products, and diagnostic 
radiopharmaceuticals added to drug products and monoclonal antibodies that 
target specific receptors) may have a common indication and certain general 
safety characteristics.  Within a class also there may be different doses, different 
risk profiles, or other unique labeling.  Further, within a broad imaging class there 
may be different characteristics as the class evolves; e.g., changes in chelates, 
carriers, ligands, or other features of the imaging drug.  As new generations of 
imaging drugs are approved, their indications may be different. 
 
In designing a trial for a class of FDA approved drugs, FDA recommends that the 
design(s) include features to address differences as appropriate within the class of 
imaging drugs.  Also, it would be important to consider what is different about the 
new indication or patient population.26  It may be necessary to determine how the 
                                                 
26 Most imaging drug classes (e.g., gadolinium, microbubbles, and radiopharmaceuticals) have a Black Box 
Warning regarding different types of serious adverse events.  The clinical trial design should consider the 
relevance of the existing safety profile to the proposed new use.  For example, magnetic resonance imaging 
of the renal arteries using an approved drug that has known toxicity in patients with renal insufficiency, the 
combined use raises new questions of safety and effectiveness of using the drug in a different risk 
population than that provided in the approved drug label for brain imaging. 
 19 Contains Nonbinding Recommendations 
device should be used with imaging drugs that have different dosing 
requirements.  These data should be established in early studies, before 
determining the pivotal trial design to establish imaging drug dosing or device 
energy differences that should be in labeling to ensure safety and effectiveness.  
Alternatively, imaging device developers may consider establishing an indication 
for only one imaging drug in a class.    
 
2.  Imaging Device Class Considerations 
 
Imaging devices typically have similar indications or intended use.  However, 
within an imaging drug class there may be differences that should be considered 
in developing the device settings to ensure consistent performance characteristics.  
Also, there may be device settings that should be preset and locked for safety and 
effectiveness.  For imaging drug manufacturers considering a new imaging 
contrast indication for a class of devices, FDA recommends considerations of 
clinical trial designs that study the similarities and differences in the class of 
marketed imaging devices that are most appropriate for the new indication.  Also, 
it is important to consider what imaging device changes have occurred since your 
imaging drug was first approved.  For the new imaging contrast indication, FDA 
also recommends considering trial designs that encompass both the most recently 
cleared/approved imaging devices as well as those that are most widely available. 
 
 
XI.   POSTMARKET CONSIDERATIONS 
 
 
The holder of an approved device submission that includes the specific new imaging 
contrast indication should monitor the approved drugs labeling as well as other changes 
to the drug.  In certain instances, FDA may require such monitoring or other postmarket 
surveillance related to the drug upon approval or clearance of the device submission.27    
Further, to enhance postmarket safety reporting, while many imaging device and imaging 
drugs do not meet the definition of a combination product, the reporting principles for 
combination products may be useful to sponsors whose labeling includes the use of a 
differently regulated product and who may receive reports about that differently regulated 
product.28  
 
 
XII.  INTERACTION WITH FDA AND THE REVIEW PROCESS  
 
 
Early communication and discussion between manufacturers and FDA should include 
concurrent discussion with the centers and, as appropriate, OCP.  Early dialogue allows 
manufacturers to obtain initial feedback on the kinds of preclinical and clinical data that 
may be necessary for their product and proposed new imaging contrast indication.  Such 
                                                 
27 21 CFR Part 803, 814.82, 822. 
28 FDA published postmarket safety reporting requirements for combination products; Federal Register, 
Vol 74, No 189, October 1, 2009, page 50744.   
 20 Contains Nonbinding Recommendations 
communication may identify critical issues for product development and help to ensure 
an efficient development and approval process.  Further, early and frequent 
communication provides the opportunity for FDA to establish its intercenter review team 
and to develop the appropriate scientific expertise to facilitate timely and efficient 
reviews of any future submissions.   
 
FDA strongly encourages a manufacturer who is considering medical imaging 
development for use with a class of imaging products to contact the center that typically 
regulates its product to request preliminary intercenter guidance.  CBER, CDER and 
CDRH provide guidance on milestone/collaboration meetings throughout the 
development process and submission of investigational and marketing applications.  Pre-
investigational (pre-IND and pre-IDE) meetings are particularly useful for discussing 
innovative combination products.29  Ideally the meeting background package should 
provide a comprehensive discussion of the proposed imaging contrast indication, the 
device technology, a copy of the existing drug labeling, and outline of the type of clinical 
studies being proposed.  During ongoing development, pre-marketing submission 
meetings are also helpful to discuss marketing application content, as well as the 
sequence and timing of modular submissions or when more than one marketing 
submission will be provided for the combination product.  Guidance on how to arrange 
developmental meetings can be obtained on the CDER,30 CBER,31 and CDRH32 
websites.    
 
The manufacturer should contact the lead center to schedule meetings in accordance with 
the milestones applicable to the lead center.  The lead center will consult with other 
centers or agency components as needed in accordance with the scientific and technical 
issues in the submission.  As described further in Section V.A Determination of Lead 
Center Responsible for Premarket Review, for device manufacturers who are considering 
trials to add new imaging contrast indications using a class of imaging drugs, the lead 
center would be CDRH.  For a combination product, the lead center is determined by the 
primary mode of action.33 
 
OCP is available formally or informally to address jurisdictional, developmental, 
premarket review, cross-labeling, and postmarket regulatory consistency issues.  Also, 
OCP is available to provide guidance for products that do not meet the definition of a 
combination product, but raise similar questions.  During product development, protocol 
                                                 
29 IND stands for investigational new drug application; IDE stands for investigational device exemption. 
30 See http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
31 See 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/defa
ult.htm  
32 See 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm and, 
Early Collaboration Meetings Under the FDA Modernization Act, Final Guidance for Industry and CDRH 
Staff; 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm073604.htm 
33 When the imaging drug and device meet the definition of a combination product, the labeling principles 
in this document would not affect the lead center assignment based on the primary mode of action.  The 
principles affect only which label should contain the new information. 
 21 Contains Nonbinding Recommendations 
design, submission coordination, and labeling, the reviewing centers intend to 
consult/collaborate in making these assessments, as appropriate.  FDA further intends to 
rely on its existing SOPP for Intercenter Consultative and Collaborative Review 
Process34 to promote timely and effective review.  
 
As appropriate, OCP will assist in developing additional focused procedures for the 
imaging review divisions/branches.  These procedures should provide for an Intercenter 
Imaging Team to review clinical protocols, labeling and other practices to ensure 
consistency of developmental approaches and relevance of results to submit under either 
the drug, biological, or device provisions.  The review would include, but is not limited 
to, the scientific/technical, risk/benefit, labeling, or potential interaction issues for the 
drug or drug class with the device(s).  FDA expects that such intercenter procedures will 
promote consistency in labeling and acceptability of new indications requested based on 
prior agency determinations regardless of the regulatory provisions used for approval or 
clearance.   
 
 
XIII.  HOW MAY I OBTAIN MORE INFORMATION? 
 
 
OCP is available as a resource to developers and review staff throughout the lifecycle 
(assignment, development, premarket review and postmarket regulation) of a 
combination product.  The Office can be reached at (301) 427-1934 or by email at 
combination@fda.gov.  In addition, the Office maintains an updated list of FDA guidance 
documents that developers may find helpful in the development of their products.  The 
guidance is available at the Offices Internet Website at 
http://www.fda.gov/CombinationProducts/default.htm.   
 
In addition each center maintains a guidance webpage that provides comprehensive 
information on the types of products or constituent parts regulated in the center.  For 
medical imaging drug products, the CDER Guidance webpage is accessible at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/defaul
t.htm.  The CDRH Guidance and Device Advice web page is accessible at  
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm. 
Selected specific guidance documents that may useful for imaging drugs and imaging 
devices include, but are not limited to, the following. 
 
  Applications under section 505(b)(2); 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guidances/ucm079345.pdf 
  Criteria for Significant Risk Investigations of Magnetic Resonance Diagnostic 
Devices; 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidance
Documents/ucm072686.htm  
                                                 
34 Standard Operating Procedures and Policies: Intercenter Consultative and Collaborative Review Process; 
http://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm119234.htm 
 
 22 Contains Nonbinding Recommendations 
  Early Development Considerations for Innovative Combination Products; 
http://www.fda.gov/oc/combination/innovative.pdf 
  Exploratory IND studies; 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126050.htm  
  FDA Radiological Health Program: Ultrasound Imaging; 
EmittingProducts/RadiationEmittingProductsandProcedures/MedicalImaging/
ucm115357.htm 
  Guideline for Device Master Files; 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoM
arketYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm14271
4.htm  
  Guidline for Drug Master Files; 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm122886.htm 
  FDA guidance Developing Imaging Drug and Biological Products, Part 1: 
Conducting Clinical Safety Assessments, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guidances/ucm071600.pdf; Part 2: Clinical Indications;  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guidances/ucm071603.pdf; Part 3: Design, Analysis and Interpretation 
of Clinical Studies, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guidances/ucm071604.pdf 
  Supplements to Approved Applications for Class III Medical Devices: Use of 
Published Literature, Use of Previously Submitted Materials, and Priority 
Review; 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidance
Documents/ucm080183.htm  
 
 
APPENDIX 1 -  MEDICAL IMAGING PRODUCT LABELING CONVENTIONS 
 
 
1.  Imaging drug indication statement:  Imaging drug labels typically are more specific 
and may follow the illustration below: 
 
Drug X is a [drug class] gadolinium based contrast agent indicated for 
[administration] intravenous administration in [imaging procedure] magnetic 
resonance imaging of the [body region] brain and spine to [clinical use] visualize 
lesions with abnormal vascularity in [population, age] adult or pediatric patients 
(age 2 or older) with known or suspected CNS lesions including tumors. 
 
2.  Imaging device imaging contrast indication statement:  The degree of specificity in 
the labeling of imaging devices varies.  In some instances, imaging device labeling 
refers to the approved imaging drug or drug class.  In other instances, the labeling 
identifies the use with an imaging drug but does not refer to the drug class.  In still 
other instances, the use with an imaging drug is implicit in the design of the device 
 23 Contains Nonbinding Recommendations 
software but does not explicitly appear in the labeling.  The following example may 
be used for a device indication statement: 
 
Device Y is indicated for [imaging procedure] magnetic resonance imaging of the 
breast with [drugs X, Y, Z ] or [FDA approved for] as a second line (after 
mammography) diagnostic procedure [clinical use] to aid in the evaluation of 
breast lesions in patients [population] with an abnormal breast examination or an 
abnormal mammogram.  Limitations [if applicable] Device Y is not indicated for 
breast cancer screening and is not an alternative to biopsy. 
 
 
APPENDIX 2  TYPE OF MEDICAL IMAGING PRODUCTS 
 
 
Medical imaging devices are marketed under the device provisions of the Act.  Medical 
imaging drugs and biological products are marketed under the drug and biological 
provisions of the Act.   
 
Most imaging drugs are modality specific and chemically distinct from one another.35  
For example:  
 
  X-ray and CT imaging drugs are iodine-containing compounds that in part are 
specifically designed to absorb x-rays. 
  MRI imaging drugs contain paramagnetic metallic ions, most commonly 
gadolinium, iron or manganese.  These imaging drugs are designed in part to alter 
the magnetic properties of water present in the body. 
  US imaging drugs typically consist of a gas contained within a lipid or protein 
shell (i.e., microbubbles or related microparticles).  These products are designed 
in part to reflect sound waves. 
  Nuclear imaging drugs, also known as radiopharmaceuticals, contain in part a 
radionuclide that exhibits spontaneous disintegration of unstable nuclei with the 
emission of nuclear particles or photons.  
  Light sensitive (emitting, absorption) imaging drugs contain molecules for 
activation by electromagnetic energy or light at specific wavelengths. 
 
In addition to these general properties, these imaging drugs are specifically formulated to 
interact with the body to facilitate imaging.  For example, some bind to receptors, interact 
with a metabolic pathway, cross abnormal blood brain barriers, or are engulfed by 
macrophages.  
                                                 
35 For purposes of this document, the term imaging or contrast drug applies to both drug and biological 
product including radiopharmaceutical products. 
 24