Clinical Trial Imaging 
Endpoint Process 
Standards 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
April 2018 
Clinical/Medical 
   
Clinical Trial Imaging 
Endpoint Process 
Standards 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
and/or 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, rm. 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
April 2018 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  LOGISTICAL AND TECHNICAL CONSIDERATIONS ........................................... 3 
A.  Choice of Imaging Modality .......................................................................................................... 3 
B.  Is Centralized Image Interpretation Important for an Imaging-Based Primary Endpoint? . 3 
C.  Should Image Interpretation Be Blinded to Clinical Data? ....................................................... 4 
D.  How Often Should Imaging Evaluations Be Performed? ........................................................... 5 
E.  How Soon After Acquisition Should Images Be Interpreted? ................................................... 5 
F.  What Procedures Should Be Standardized for an Imaging-Based Clinical Trial Primary  
  Endpoint? ....................................................................................................................................... 5 
IV.  THE EXTENT OF IMAGING PROCESS STANDARDS ........................................... 7 
A.  Are Existing Medical Practice Imaging Process Standards Sufficient for the Trials Primary  
  Endpoint? ....................................................................................................................................... 7 
B.  What Should Be Considered When Augmenting Existing Medical Practice Imaging Process  
  Standards to Create Trial-Specific Imaging Process Standards? ............................................. 7 
REFERENCES .............................................................................................................................. 9 
APPENDIX A:  BEFORE IMAGING:  CHARTER CONSIDERATIONS ......................... 10 
APPENDIX B:  DURING IMAGING:  MONITORING PLANS AND CHARTER 
MODIFICATIONS ..................................................................................................................... 27 
APPENDIX C:  AFTER IMAGING:  DATA TRANSFER, ARCHIVING, AND 
ANALYSIS OF IMAGING INFORMATION ......................................................................... 28 
 
  Contains Nonbinding Recommendations 
Clinical Trial Imaging Endpoint Process Standards 
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION 
 
The purpose of this guidance is to assist sponsors in optimizing the quality of imaging data 
obtained in clinical trials intended to support approval of drugs and biological products.2  This 
guidance focuses on imaging acquisition, display, archiving, and interpretation process standards 
that we regard as important when imaging is used to assess a trials primary endpoint or a 
component of that endpoint.   
 
Considerable standardization already exists in clinical imaging.  There are a variety of sources, 
including picture archiving and communication systems and the Digital Imaging and 
Communications in Medicine (DICOM) formats for the handling and transmission of clinical 
imaging information that describe the standards generally employed by clinical practitioners.  
This guidance recommends additional imaging endpoint process standards that are more specific 
to clinical trials.  Imaging process standards help sponsors ensure that imaging data are obtained 
in a manner that complies with a trials protocol, that the quality of imaging data is maintained 
within and among clinical sites, and that a verifiable record of the imaging process is created.  
Minimization of imaging process variability may importantly enhance a clinical trials ability to 
detect drug treatment effects.   
 
Standardization, while important for all clinically used measures, becomes essential for an 
imaging endpoint used in a clinical trial to reduce variability and to ensure interpretability of the 
results.  The extent of trial-specific standardization may vary depending upon how standardized 
the local imaging procedures are (e.g., routine bone X-rays (relatively standardized) versus bone 
mineral density (more variability across sites)).  This guidance does not address approaches for 
                                                 
1 This guidance has been prepared by the Division of Medical Imaging Products in the Center for Drug Evaluation 
and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
  1  Contains Nonbinding Recommendations 
selecting an imaging endpoint for a clinical trial.  An imaging endpoint, even if standardized and 
considered to be precise and accurate, might not be interpretable if it does not have clinical 
meaningfulness (e.g., hip fracture versus changes in local blood flow in the central nervous 
system detected by positron emission tomography (PET) imaging). 
 
This guidance does not address whether specific imaging measures would be acceptable in 
submissions used to support approval of a drug or biologic.  These considerations should be 
discussed with the FDA review division responsible for drug development.   
 
Many of the imaging process standard considerations for clinical trials of therapeutic drugs can 
also be applied to clinical trials that evaluate the performance of diagnostic drugs.  For 
considerations involving the development of diagnostic imaging drugs, see the guidance for 
industry Developing Medical Imaging Drug and Biological Products (Parts 1, 2, and 3).3 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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.  BACKGROUND 
 
Almost all medical imaging processes involve some aspects of standardization established by 
those within the practice of medicine.  In medical practice, images of human anatomy and/or 
physiology typically are acquired and interpreted, often with limited or no formal quantification, 
by a single facilitys imaging professional staff.  The images typically achieve the medical 
practices diagnostic purposes even though the acquisition, display, and interpretation methods 
may vary somewhat among imaging facilities and imaging professionals.  This variability may 
have little or no impact on the ability to provide a diagnosis in medical practice, yet in a clinical 
trial, imaging process variability may result in increased variability in endpoint measurements 
and may compromise the ability of the trial to achieve its objectives.   
 
Although the medical practice of diagnostic imaging already follows many standardized 
procedures, we recommend that some trials augment these existing standards to create trial-
specific imaging process standards.  For purposes of this guidance, we define these trial-specific 
imaging process standards as standards that extend beyond those typically performed in the 
medical care of a patient (i.e., the process standards are implemented solely for the purposes of 
the clinical trial).  The extent of trial-specific imaging process standards can range from minimal 
processes that are described solely in the clinical protocol, such as obtaining noncontrasted and 
contrasted images in all subjects, to more detailed imaging process standards for image 
acquisition, display, interpretation, and archiving that are detailed in an imaging charter (see 
Appendixes A through C). 
 
                                                 
3 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
  2  Contains Nonbinding Recommendations 
A clinical trials design and clinical context are critical determinants of the extent that imaging 
process standards could be important to the trial. In a clinical trial where the imaging process and 
imaging primary endpoint measures are not well standardized in medical practice, trial-specific 
standards become important.    
 
The following sections outline the imaging process topics that sponsors should address when an 
imaging primary endpoint is used within a clinical trial intended to support the approval of a 
proposed drug.4   
 
 
III.  LOGISTICAL AND TECHNICAL CONSIDERATIONS 
 
The following subsections describe some of the factors a sponsor should assess when 
considering the use of an imaging-based primary endpoint in a clinical trial intended to support 
approval of a drug.  The sponsor should contact the assigned FDA review division to discuss the 
clinical meaningfulness of the primary endpoint imaging information to be obtained in the trial. 
 
A.  Choice of Imaging Modality 
 
If an imaging-based primary endpoint is chosen for a phase 3 trial, the choice of the imaging 
modality (such as echocardiography versus single photon emission computerized tomography) 
may prove to be an especially important consideration.  Imaging modality upgrades and 
malfunctions are sometimes unpredictable.  Clinical sites may also experience unforeseen 
limitations on the use of the modality or modality-specific imaging drugs and processes, such as 
the interchange of certain contrast agents that may not affect typical diagnostic imaging but may 
alter trial-specific quantitative imaging measures.  
 
B.  Is Centralized Image Interpretation Important for an Imaging-Based 
Primary Endpoint? 
 
In clinical trials, images are interpreted either at the clinical site or at a centralized facility that 
receives images from the clinical sites.  Sometimes, both site and centralized imaging 
interpretation may be performed.  Image interpreters are sometimes referred to as readers, and 
we use that term in this guidance.5 
 
The usefulness of a centralized image interpretation process is determined by the role, 
variability, and susceptibility to bias of imaging within the trial as well as modality-specific 
image quality considerations and overall trial design features.  Centralized image interpretation is 
not always critical, even for a phase 3 trial primary endpoint that uses some aspects of 
quantitative imaging, if the quantitative measures are widely performed and reported in clinical 
medicine, little imaging acquisition or interpretation variability is anticipated, and potential 
                                                 
4 Evidentiary standards for diagnostic imaging products are addressed in parts 2 and 3 of the guidance for industry 
Developing Medical Imaging Drug and Biological Products (Parts 1, 2, and 3). 
 
5 Terms such as image interpretation, image review, or image read are used interchangeably in this guidance, and in 
literature and protocols, image readers are sometimes referred to as image reviewers. 
  3  Contains Nonbinding Recommendations 
biases in image interpretation are controlled by the trial design features.  However, these 
characteristics may not apply to some clinical trials, such as those that might be subject to bias 
and cannot be blinded, those that use imaging modalities vulnerable to image quality problems, 
and those that use specialized imaging measures.   
 
In open-label clinical trials, availability of clinical information might influence a site-based 
image interpretation because the expected relation of clinical features to outcome is known, and 
therefore, a site-based image interpretation could raise concern about potential bias.  A 
centralized image interpretation process, fully blinded, may greatly enhance the credibility of 
image assessments and better ensure consistency of image assessments.  Some imaging 
modalities also may prove vulnerable to site-specific image quality problems, and a centralized 
image assessment process may help minimize these problems.  For example, the National Lung 
Screening Trials experience with computed tomography of the chest suggested that centralized 
image quality monitoring was important to the reduction of imaging defects (Gierada, Garg, et 
al. 2009).  Hence, a centralized image interpretation process may be used to help control image 
quality as well as to provide the actual imaging-based endpoint measurements. 
 
Some image interpretation methods, such as trial-specific measures of bone or joint disease in 
arthritic diseases, rely upon centralized imaging because of the extent of reader training 
recommended for the specialized image interpretation.   
 
As compared to site-based image interpretations in multicenter clinical trials, a centralized image 
interpretation process may provide more verifiable and uniform reader training as well as 
ongoing management of reader performance, helping to ensure quality control of the images and 
the interpretations and to decrease variability in image interpretations, leading to a more precise 
estimate of treatment effect.  Nevertheless, the overarching trial design features and the other 
previously described features may justify the use of site-based imaging interpretations even in 
large phase 3 multicenter clinical trials, so long as blinding of image interpretation to treatment 
can be assured or bias is otherwise controlled. 
 
C.  Should Image Interpretation Be Blinded to Clinical Data? 
 
The extent of blinding image readers to clinical data depends upon the role of imaging in the 
clinical trial, the specific disease and clinical setting, and the potential for unblinding effects 
(e.g., toxicity) of the investigational drug.  In a randomized controlled trial, we expect that 
clinical trial primary endpoint image readers will be blinded to a subjects treatment assignment 
because knowing the assignment would be presumed to create bias.  Further, we anticipate that 
many, if not most, clinical trials using imaging-based primary endpoints will be conducted with 
no reader knowledge of individual-level clinical data because this knowledge also may bias the 
reader.  In unique situations, a primary endpoint might rely upon integration of clinical data into 
an image interpretation (Sargent, Rubinstein, et al. 2009).   
 
To determine whether image readers should be blinded to clinical information, sponsors should 
have knowledge of the underlying clinical condition, an understanding of the precedent for the 
use of imaging as a trials primary endpoint, and detailed insight into the trials unique image 
interpretation procedures (such as a plan for sequential locked-read image interpretation where 
  4  Contains Nonbinding Recommendations 
an assessment cannot be altered versus an option for modification of prior image interpretations).  
In certain disease conditions, readers also should be blinded to the image acquisition date and/or 
knowledge of prior imaging observations.  Again, we note that even if the image reader is aware 
of individual-level clinical information, blinding to treatment assignment is almost always 
critical. 
 
D.  How Often Should Imaging Evaluations Be Performed? 
 
When a medical image serves as a trials primary endpoint, its timing and frequency of 
ascertainment depends upon the underlying condition being studied, the feasibility of the 
imaging schedule, and the overarching trial design features.  For a trial using time point-based 
imaging measures as a primary endpoint, the frequency of imaging evaluations should be the 
same in all trial arms.  Asymmetric imaging evaluation time points can introduce bias in the 
treatment effect assessment. For a primary endpoint that uses a time-to-event analytical 
approach, imaging evaluations should be performed at baseline and at sufficient frequency to 
provide a reasonably precise measure of the time to the expected clinical event.   
 
E.  How Soon After Acquisition Should Images Be Interpreted? 
 
In diagnostic medical imaging practice, images typically are interpreted on site within several 
hours following acquisition.  In contrast, in clinical trials using centralized imaging 
interpretation, the interpretation may require a longer time frame.  Therefore, image 
interpretation timing typically is more of a consideration when clinical trials use centralized 
imaging interpretation.  When planning a clinical trial that uses an imaging primary endpoint, the 
turnaround time by a central image interpretation facility should be appropriate for the 
anticipated trial design.  For example, prompt image interpretation may be an important 
consideration for trials that use centralized image interpretations as components of interim 
analyses, which may occur when imaging-based analyses are important to accommodate 
prespecified sample size adjustment plans.  Similarly, image interpretation expediency may 
prove critical when centralized imaging interpretation is used to help control imaging quality; in 
this situation, the centralized imaging readers or an appropriately prespecified centralized 
imaging quality control process should promptly identify technical flaws that necessitate repeat 
imaging of a subject.  In other circumstances, interpretation of batches of randomized images at 
specified intervals during a trial may be appropriate.  Sponsors should consider the timeliness of 
centralized image interpretation when developing a clinical trial protocol that uses an imaging-
based primary endpoint. 
 
F.  What Procedures Should Be Standardized for an Imaging-Based Clinical 
Trial Primary Endpoint? 
 
No single set of detailed imaging process standards is readily applicable to every clinical trial 
because the trials differ in design and objectives.  When usual medical practice imaging process 
standards are acceptable in a trial, the plans for the use of such standards should be stated in the 
clinical protocol.  Determinations on what to standardize beyond these expectations should be 
driven by consideration of the imaging processes that might introduce variability and inaccuracy 
to the endpoint and by consideration of the other items outlined below.  When determining the 
  5  Contains Nonbinding Recommendations 
extent of imaging process standardization critical for a phase 3 clinical trial that uses an imaging-
based primary endpoint, sponsors should consider the following factors:   
 
  Imaging modality availability and the modalitys technical performance variation across 
trial sites 
 
  Performance features of the imaging modality at the trial sites or any other locations 
where subjects may undergo imaging 
 
  Qualifications of the imaging technologists and any special technological needs for the 
trial 
 
  Proposed imaging measures reliance on phantoms and/or calibration standards to ensure 
consistency and imaging quality control among clinical sites 
 
  Any unique image acquisition features of the trial design, including subject positioning, 
anatomical coverage of imaging, use of contrast, timing of imaging, importance of 
subject sedation, and scanner settings for image acquisition 
 
  Image quality control standards, including those specifying the need for repeat imaging to 
obtain interpretable images 
 
  Procedures for imaging display and interpretation, including technical variations in reader 
display stations 
 
  Nature of the primary endpoint image measurement, including the importance of training 
image readers in trial-specific quantification methods 
 
  Extent that image archiving could be important to the trials conduct, monitoring, and 
data auditing 
 
  Potential for imaging modality upgrades or modality failures, as well as the potential 
variation in imaging drugs (such as contrast agents) across trial sites 
 
  Precedent for use of the imaging-based primary endpoint measure in investigational drug 
development, especially previously observed imaging methodological problems   
 
If the existing medical imaging practice standards should be augmented to create trial-specific 
imaging process standards and those trial-specific standards are too lengthy to be described in the 
clinical protocol, then we encourage sponsors to develop an imaging charter that details the trial-
specific imaging process standards (see Appendix A).  An imaging charter can consist of a single 
document or a series of technical documents.  Overall, the charter should describe how potential 
sources of imaging bias and variability are controlled and how imaging process standards are 
implemented to a level appropriate to the trial design.   
 
 
  6  Contains Nonbinding Recommendations 
IV.  THE EXTENT OF IMAGING PROCESS STANDARDS 
 
The extent of imaging process standards in a phase 3 clinical trial runs on a continuum from the 
standards already in place in imaging medical practice to trial-specific considerations of image 
acquisition, display, transmission, interpretation, database development, and archiving.  
Similarly, the effort associated with clinical trial imaging standardization may range from 
relatively minor to challenging.  At a minimum, the sponsor should consider the following 
questions when developing primary endpoint imaging process standards for a clinical trial. 
 
A.  Are Existing Medical Practice Imaging Process Standards Sufficient for the 
Trials Primary Endpoint? 
 
To rely solely on existing medical practice imaging process standards to support an imaging-
based clinical trial primary endpoint, the sponsor should anticipate the variability inherent in 
clinical site-based image acquisition, display, interpretation, and archiving.  Consequently, for 
sponsors to rely solely on existing imaging process standards, the trials imaging endpoint 
measure or outcome should be readily apparent on an image that is acquired, displayed, and 
interpreted using imaging processes that do not importantly vary among clinical sites.  For 
example, existing medical practice imaging process standards may be reasonable for an endpoint 
focused upon the detection of a long bone fracture or intracranial hemorrhage  an indisputable 
outcome that is readily determined with well-accepted and widely implemented imaging 
methods that do not importantly vary among clinical sites.   
 
With medical practice imaging process standards, the images might be interpreted and archived 
at the clinical site such that the imaging outcome may be documented in the clinical trial records 
solely by an investigators response on a case report form and/or appended clinical imaging 
report.  This type of image documentation typically is insufficient for a clinical trial endpoint that 
relies upon quantitative imaging assessment unless the quantitative measure is widely accepted 
as reliable and consistently reported to clinicians as a component of medical practice.  The more 
complex the image endpoint quantification process, the more likely the existing medical practice 
imaging process standards will not be sufficient and will necessitate trial-specific standards that 
minimize variability and document image endpoint measurements.  
 
B.  What Should Be Considered When Augmenting Existing Medical Practice 
Imaging Process Standards to Create Trial-Specific Imaging Process 
Standards? 
 
We anticipate that most phase 3 clinical trials using an imaging-based primary endpoint will 
benefit from some aspect of trial-specific imaging process standardization.  In some situations, 
this standardization may be confined to a clinical protocols brief statement about the nature of 
the imaging to be performed in the trial and the frequency of the imaging evaluations.  For 
example, the protocol may include a statement that all subjects will be imaged both with and 
without contrast enhancement.  In other situations, an imaging charter should be developed to 
standardize an array of imaging procedures among the clinical sites, such as the timing of 
imaging during the trial, details of contrast injection, subject sedation and positioning, image 
display and interpretation, and image archiving.  Appendix A describes the various components 
  7  Contains Nonbinding Recommendations 
of imaging process standards a sponsor should consider when augmenting medical practice 
imaging processes.  In comparison to medical practice imaging process standards alone, trial-
specific standards may provide better assurances that the imaging methods for the assessment of 
a trial imaging endpoint are well defined and reliable.6   
 
                                                 
6 See 21 CFR 314.126(b)(6). 
  8  Contains Nonbinding Recommendations 
REFERENCES 
 
Dogan, S, Y Plantinga, J Crouse, et al., 2011, Algorithms to Measure Carotid Intima-Media 
Thickness in Trials:  A Comparison of Reproducibility, Rate of Progression and 
Treatment Effect, J Hypertens, 29(11):218193. 
  
Eisenhauer, E, P Therasse, J Bogaerts, et al., 2009, New Response Evaluation Criteria in Solid 
Tumors:  Revised RECIST Guideline (version 1.1), Eur J Cancer, 45(2):22847.  
 
Gierada, D, K Garg, H Nath, D Strollo, R Fagerstrom, and M Ford, 2009, CT Quality Assurance 
in the Lung Screening Study Component of the National Lung Screening Trial:  
Implications for Multicenter Imaging Trials, Am J Roentgenol, 193(2):41924. 
 
Keen, H, P Mease, C Bingham, J Giles, G Kaeley, and P Conaghan, 2011, Systematic Review of 
MRI, Ultrasound, and Scintigraphy as Outcome Measures for Structural Pathology in 
Interventional Therapeutic Studies of Knee Arthritis:  Focus on Responsiveness, J 
Rheumatol, 38(1):14254. 
 
Krupinski, E, K Berbaum, R Caldwell, K Schartz, M Madsen, and D Kramer, 2012, Do Long 
Radiology Workdays Affect Nodule Detection in Dynamic CT Interpretation?, J Am Coll 
Radiol, 9(3):19198. 
 
Sargent, D, L Rubinstein, L Schwartz, J Dancey, C Gatsonis, L Dodd, and L Shankar, 2009, 
Validation of Novel Imaging Methodologies for Use as Cancer Clinical Trial End-points, 
Eur J Cancer, 45(2):29099. 
 
 
  9  Contains Nonbinding Recommendations 
APPENDIX A:  
BEFORE IMAGING:  CHARTER CONSIDERATIONS 
 
This appendix outlines some of the imaging methodology factors FDA recommends for sponsors 
who may be considering using specific imaging standards for a particular clinical trial.  We refer 
to these augmented imaging process standards as trial-specific standards.  Relatively 
uncomplicated trial-specific standards can be described in the body of a clinical protocol.  If the 
trial-specific standards are too extensive for a clinical protocol, a separate imaging charter may 
be more appropriate.    
 
An imaging charter (hereafter, charter) can consist of either a single document or a series of 
documents.  The charter should describe the clinical trial imaging methodology, including 
modality-specific technical details, image interpretation, and image archiving procedures.  
Sponsors should develop the document or documents with the same rigorous standards typically 
applied to the clinical protocol.  Indeed, sponsors can choose to develop the charter as an 
appended component of a clinical protocol.  In this situation, the charter can be attached to a 
clinical protocol as an appendix or cited as a supplementary document.  The charter can also 
consist of a freestanding, overarching summary of the imaging methodology with references to 
multiple other imaging-specific documents that form a component of the charter, such as 
imaging acquisition protocols, data transfer plans, or image submission guidelines.  These 
documents should provide detailed information on the methodology for acquiring images and for 
transferring and archiving the images and the image interpretation data. 
 
Generally, we do not regard the charter as part of the protocol unless the sponsor specifically 
designates it as a component.  We encourage sponsors to submit the charter for FDA review and 
to do so as soon as possible.  In the unusual situation where review of a charter is critical for 
completing either a special protocol assessment or review of a trials clinical protocol, the review 
division can specifically request submission of the charter along with the trials clinical protocol.  
Submission of a charter for FDA review helps to support the plan for verification of the trials 
data integrity because compliance with the charter may form an important aspect of the trial 
conduct verification process as well as of the data quality assessment procedure. 
 
When imaging forms an important part of a phase 3 clinical trials primary endpoint (or some 
other important part of a trial), we encourage sponsors to briefly discuss at an end-of-phase 2 
meeting whether or not imaging standardization procedures are appropriate.   
 
There is no specific format or content recommended for a charter.  When developing a charter, 
sponsors should define the requirements for standardization based on the trials imaging 
objectives and the sponsor-required imaging methods at the participating clinical sites.  
Consequently, sponsors should specify key requirements for imaging equipment and image 
quality, as well as the processes for image acquisition, display, interpretation, storage, and data 
transfer.   
 
Imaging technology evolves rapidly and can be highly technical.  The complexity of technical 
standardization may markedly limit the use of imaging in a multicenter clinical trial even if the 
imaging methods have well-recognized value in clinical medicine (Keen, Mease, et al. 2011).   
  10  Contains Nonbinding Recommendations 
 
Listed below are the suggested headings and subheadings for the elements within a charter.  
Some of these elements may not apply to a particular clinical trial.  We encourage sponsors to 
address each of these elements within their charters in a manner most appropriate for the trial.   
 
Executive Summary of the Trial Design and the Role of Imaging in the Trial 
 
The charter should summarize the role of imaging within the clinical trial and provide a 
description of the imaging database variables (deliverables) to be incorporated into the analysis 
of the primary endpoint.  It should address important trial design features detailed in the protocol 
that might affect the proposed imaging database variables (e.g., procedures to minimize missing 
data, plans for the use of off-protocol images).   
 
The executive summary should also provide an overview of the major aspects of the image 
acquisition, interpretation, and reader-defined deliverables.  Presentation of a flow chart that 
identifies the specific steps in the process can be especially useful in summarizing the flow of the 
imaging information. 
 
Standards for Image Acquisition  
 
Development of image acquisition standards involves a broad knowledge of imaging modalities, 
including knowledge of anticipated imaging equipment upgrades or malfunctions during the 
conduct of the clinical trial.  In some situations, exploratory clinical trials may be critical to 
identify the most important imaging technical details, including those vulnerable to technical 
factors and charter noncompliance.  For example, an explicit description of the imaging 
acquisition time may be critical when rapid dynamic cardiac arteriography is used to assess 
coronary artery disease; in this situation, the X-ray energy (kVp) should be standardized and be 
considered appropriate for imaging iodinated contrast agent within the heart.  Similarly, 
optimization of X-ray energy is essential for breast imaging because a high kVp will obscure the 
signal intensity differences between adipose, glandular, or cancerous tissue, and variations in 
kVp among clinical sites may increase variability in the imaging endpoint.  In addition to 
equipment settings, other imaging acquisition parameters critical to the trial imaging endpoint 
(e.g., the number, angle, and magnification level of radiographic views in assessing arthritis) 
should be standardized in the charter.  The feasibility of maintaining technical consistency within 
and among clinical sites is particularly important when choosing and optimizing the imaging 
modality.   
 
Equipment Standardization and Operation 
 
The charter should typically identify the following:  
 
  Vendor-specific equipment/platforms (e.g., injectors, scanners, ultrasound probes, 
software).  The charter should identify the use of any investigational equipment.  For 
sites in the United States, we recommend the use of imaging equipment that has received 
FDA marketing authorization.  Use of investigational devices is subject to the 
requirements of 21 CFR part 812 governing investigational device exemptions.  
  11  Contains Nonbinding Recommendations 
 
The charter should specify the important imaging equipment for the trial, including the 
imaging drug (contrast) injectors, scanners, ultrasound probe selection/settings, and 
software.  This is particularly important for certain functional and quantitative imaging 
tasks that benefit from the use of specific scanners and models that are able to perform 
the imaging and allow the control that ensures the standardization.  The importance of the 
equipment specifications varies with the role of imaging in the trial and may limit the 
number of qualifying clinical sites.  For example, imaging scanners may differ in 
technical details that can influence image quality, such as image reconstruction software 
programs and techniques for respiratory and cardiac gating, subject positioning, scan 
times, probe positioning, and technician-dependent procedures.   
 
In trials using quantitative imaging procedures, an ongoing site qualification process may 
be important to maintain control of changes in imaging hardware and software.  In other 
trials (e.g., large multinational trials using standard computed tomography or magnetic 
resonance imaging modalities), the ongoing control of hardware and software versions 
across all sites may be inapplicable or impractical.  The charter should provide a 
justification for the approach proposed by the sponsor.  The sponsor can provide routine 
extensive technical details in companion manuals (e.g., imaging acquisition and 
processing manuals) rather than in the charter. 
 
In situations where minimizing variability of imaging data is critical, we encourage the 
use of a tabular listing of the acceptable imaging equipment, including the key 
characteristics of the acquisition, processing, and display components of each scanner or 
review workstation.  Another approach could be to identify the physical benchmarks and 
testing parameters that should be met by the imaging equipment in accordance with a 
prespecified protocol for the acquired images to be used in the trial.  When developing 
these specifications, sponsors are encouraged to perform exploratory analyses of imaging 
outcomes grouped by imaging platforms. 
 
Most three-dimensional imaging technology relies upon raw data processing using 
proprietary software algorithms.  Software upgrades within the trial period may affect 
how images are generated.  Changes in an image may be caused by these software 
changes and be incorrectly attributed to actual clinical changes.  The charter should 
specify minimum requirements for important software and also identify any situations 
when alternatives are acceptable.   
 
Occasionally, requisite imaging equipment may become unavailable at a qualified site 
because of equipment malfunction or unavailability of technical support.  In these 
situations, a clinical site might choose to substitute one imaging modality for another 
(such as magnetic resonance for computed tomography).  The charter should identify the 
situations when these changes are acceptable.  We anticipate that, in many situations, 
modalities will not prove interchangeable (such as arteriography for ultrasound) when the 
endpoint assessment involves a quantitative imaging measurement.  Ad hoc, unplanned 
interchange of modalities (including substitution of film for digitized imaging data) may 
  12  Contains Nonbinding Recommendations 
compromise trial objectives if changes occur for a given subject during the course of the 
clinical trial. 
 
  Equipment technical settings to be used at each site.  The charter should summarize 
the technical settings for image acquisition for each type of important imaging equipment 
and should identify any acceptable deviations from these settings.  We encourage 
sponsors to identify these settings based upon the findings from exploratory clinical trials 
or other trials that attempted to standardize the technology among multiple clinical sites.  
Typically, such information is included in site imaging manuals.  Details critical to 
quantitative imaging, such as tomographic slice thickness, pulse sequence, and contrast 
agent injection time (especially for dynamic imaging), should be specified in the charter. 
 
  Role of site imaging technicians in equipment operation, including the identification 
of faulty or unacceptable images and the importance of repeating imaging.  The 
charter should describe the role of the imaging technician in the image acquisition 
process, including the recommended qualifications and the role of the technician, if any, 
in the initial assessment of image quality.  Situations should be identified when repeat 
imaging is critical (and exposure to additional radiation dose is justified) because 
technical failure has made the images uninterpretable.  In some situations, such as 
ultrasound imaging, detailed procedures should describe the technicians role in 
manipulation of the imaging probe.  Depending upon the imaging modality and the 
technical demands, the charter can describe or reference the trial documents describing a 
technician training process that will help ensure consistency in image acquisition.  In this 
situation, the charter should specify that administrators of trial sites will document 
modality-specific training standards and maintain records that show the technologists 
participating in the trial have met all training requirements specified by the charter.  
 
  Phantoms to be used for site qualification and image quality monitoring.  In many 
situations, the use of phantoms (i.e., prespecified objects for scanning) is a critical part of 
site qualification and image quality monitoring during the conduct of a clinical trial.  In 
other situations, phantoms may not be important if the equipment and imaging 
acquisition parameters are well standardized.  Phantoms can simulate a variety of 
conditions and have been developed for a range of imaging modalities (e.g., magnetic 
resonance, nuclear medicine, radiography).  The choice of the specific phantom type 
depends upon the imaging objectives as well as upon the specific imaging modality.  
Standardization of image acquisition using imaging and dosimetry phantoms often 
enhances the consistent performance of the imaging equipment during the course of the 
trial.   
 
  Subject preparation, positioning, and comfort measures.  Many imaging modalities 
require specific subject preparation (e.g., fasting, special dietary limitations), positioning 
(e.g., supine, right lateral decubitus, weight-bearing status for lower extremity 
radiographs), preparation (e.g., removal of jewelry and eyeglasses), and comfort 
measures (e.g., ear plugs, sedation).  These common aspects of imaging could vary 
markedly among clinical sites.  The charters specifications for these items may prove 
especially useful because significant site-to-site variations in subject preparation can 
  13  Contains Nonbinding Recommendations 
result in unacceptable levels of image variability.  Subject preparation also might be 
based on subject-specific factors, such as age, weight, and physical condition; the 
importance of standardization of these aspects may widely vary.  For example, a trial 
conducted among pediatric subjects may call for some form of sedation.  A description of 
the acceptable sedatives (including doses, route of administration, and potential for repeat 
dosing) may prove essential to quality imaging as well as to the avoidance of missing 
images.   
 
  Schedule for imaging and alternatives.  Typically, a trials clinical protocol would 
outline the schedule for imaging evaluations; hence, the charter might not include the 
schedule.  In other situations, the clinical trial protocol might include only a superficial 
description of the imaging schedule, so the charter should include more details about 
imaging times.  For example, in certain circumstances, subjects should be imaged at a 
specific time of day or night or following the development of certain clinical features 
(such as pain in a joint) that prompt imaging-specific procedures (such as region-of-
interest imaging).  The charter should describe these expectations and also identify date 
and time windows that represent acceptable alternatives to the planned imaging 
evaluations. 
 
  Off-protocol imaging.  Subjects in a clinical trial lasting many months are likely to 
undergo imaging examinations in addition to the ones intended to assess the response to 
therapy or to detect disease progression.  These off-protocol images may or may not be 
made available to image readers and considered as part of the trials imaging-based 
outcomes.  The clinical protocol may address some of the off-protocol imaging plans, but 
we recommend that the charter elaborate upon these plans to clarify whether and in what 
way the off-protocol image interpretation would contribute to the trials endpoint 
assessment. 
 
  Imaging risks.  Imaging may involve risks to subjects, such as exposure to radiation and 
contrast agents.  These risks should be described in the trials clinical protocol so that 
they can be considered by institutional review boards and appropriately described within 
consent documents (see 21 CFR parts 50 and 56).  Therefore, we anticipate that most 
charters will not contain a section that describes imaging risks.  
 
Occasionally, clinical trial imaging detects incidental findings that may be important for 
further clinical evaluation.  Incidental image findings may result in health benefits as well 
as risks for subjects.  For example, some incidental findings may needlessly prompt 
invasive diagnostic evaluations.  If the detection of incidental findings is likely with 
clinical trial imaging, the clinical protocol and consent documents should describe the 
procedures for handling the incidental findings.  The charter also should summarize how 
these incidental findings will be handled based upon the description within the clinical 
protocol.  A description of these plans within the clinical protocol is important to ensure 
that the process is reviewed by institutional review boards and, as necessary, summarized 
within trial consent documents (see 21 CFR parts 50 and 56).    
 
  14  Contains Nonbinding Recommendations 
  Site qualification process.  The charter should address the process used to qualify 
clinical sites for trial participation, specifically describing and/or referencing the tests to 
be performed to verify equipment performance, technical support, and capability for 
compliance with charter expectations.  We anticipate that phantom imaging, on-site 
inspection, and/or training will provide sufficient site qualification for many trials.  In 
some situations, the site qualification process should build upon these expectations by 
imaging subjects as part of a qualifying clinical trial.  These types of site qualifications 
can be particularly important for highly technical imaging modalities or international 
trials that include countries where the imaging technology might be uncommon in clinical 
practice.   
 
  Acquisition quality control monitoring process.  The charter should describe the plan 
for periodic, quality control monitoring of imaging acquisition, storage, and transfer, 
including the plan for repetitive phantom imaging and the correction of deviations from 
the quality expectations.  The importance and nature of this type of monitoring vary, 
depending upon the nature of the imaging technology, but at a minimum, should involve 
some form of episodic imaging quality reporting from clinical sites.  In instances where 
imaging is particularly complex or novel, we recommend periodic on-site inspection by 
the trials imaging-specific monitors to assess the imaging technical compliance of each 
clinical site or a subset of all the sites.  Situations should be identified in which sites will 
be requalified or terminated because of failure to comply with image quality 
expectations.  All requalification procedures should be described.   
 
  Data storage and transfer.  The charter should describe the expectations for imaging 
data storage and transfer to any separate facility from the imaging site (e.g., centralized 
laboratory, the sponsor).  In general, the charter should do the following:  
 
  Specify the storage of imaging data at the clinical site  
 
  Describe any and all plans for transfer and storage of imaging data outside the clinical 
site 
 
  Describe any image alteration procedures to be performed at the site (such as removal 
of all subject-identifying information (i.e., anonymization)) 
 
  Specify the time period for storage of images at clinical sites and the format for data 
storage 
 
Imaging Drug Standardization  
 
Drugs are commonly used as a component of imaging and often require administration 
procedures related to the scanning of a subject.  Most notable drugs used as components of 
imaging include the following: 
 
  Preparative drugs 
  Contrast agents 
  15  Contains Nonbinding Recommendations 
  Radiopharmaceutical agents 
 
Depending upon the nature of the imaging evaluation, the charter should identify the important 
aspects of drug selection, dosage, and administration for each of these drugs, as exemplified 
below.   
 
  Preparative drugs.  In situations where preparative (or other) drugs are important for the 
planned imaging evaluations, the charter should identify acceptable and/or requisite pre-
imaging drugs, including sedatives, stimulants, beta-blockers, vasodilators, intravenous 
fluids, or contrast agents.  The drugs should be identified by their names and by dosages 
and routes of administration.  These specifications can be particularly important for trials 
in which pediatric subjects are enrolled and for the imaging of subjects following 
administration of drugs that will affect images (such as drugs essential for cardiac stress 
testing).   
 
  Contrast agents.  Many modality-specific contrast agents are not interchangeable and 
differ importantly in doses, techniques for administration, and risks.  If critical to the 
imaging evaluation, the charter should identify acceptable and/or requisite contrast 
agents, including specific names.  The charter should also identify the doses, routes of 
administration, rates of administration, and any special administration procedures (such 
as automatic injectors or administration times that may trigger scanning).   
 
Some contrast agents can be safely administered only to subjects with acceptable renal 
function or other characteristics.  The charter should identify any laboratory tests and 
outcomes critical for supporting the administration of contrast agents.  Risks associated 
with imaging, including those associated with contrast agents, are best described in the 
clinical protocol. 
 
  Radiopharmaceutical agents.  In addition to specification of the administered activity, 
mass, and route of administration, the charter should briefly identify the major drug 
quality features for any clinical trial radiopharmaceutical manufactured at clinical sites.  
Unlike preparative drugs and contrast agents, some radiopharmaceuticals (e.g., PET 
agents) are commonly produced at clinical sites, and the quality of these drugs may vary 
from site to site.  Standardization of these drug attributes may be important in achieving 
the trials imaging objectives.  The charter should identify any site-specific production 
considerations for site qualification.   
 
Standards for Image Interpretation 
 
Image interpretation generally is carried out by trained readers, such as qualified radiology, 
nuclear medicine, and/or clinical specialists, who review and interpret, or read, images obtained 
in the course of a clinical trial.   
 
The following elements pertain predominantly to the use of a centralized facility for image 
interpretation in a clinical trial.  Whether images are interpreted solely at the clinical site or at 
  16  Contains Nonbinding Recommendations 
both the clinical site and a centralized facility, we regard these elements as important aspects to 
address within the charter when a centralized facility is used.  
 
Image Transfer, Receipt Documentation, and Initial Quality Assessment  
 
The charter should identify the process for transfer of imaging data from each clinical site to the 
centralized image interpretation facility, including the plans for the following:  
 
  Verification of the image technical adequacy  
 
  Transfer of images and supportive information to the centralized facility 
 
  The centralized facility process for querying sites for missing images, data, or imaging 
technical problems 
 
  Obtaining repeat images of subjects 
 
  Logging of images received at the centralized facility, including the subject-specific 
tracking system 
 
  Formatting for image data transfer  
 
  Digitization of received images or data 
 
  Any technical evaluation (or pre-interpretation) or alteration of images, including de-
identification of subject information, biasing marks, or other undesired image signals  
 
  Monitoring compliance with the transfer, receipt, and initial image assessment process  
 
  Correction of deficiencies and failures in the transfer, receipt, or initial image assessment 
process 
 
The process should be highlighted for removal of all subject-identifying information from 
images relayed through electronic communication (e.g., Internet, laptop computers) or other 
pathways that are vulnerable to a security breach (e.g., courier or postal transfer of hard copy 
images or digital images on disk).   
 
Image Display and Interpretation  
 
The paradigm shift from film-based to filmless imaging has redefined clinicians processes of 
image display, and interpretation of images within a clinical trial may critically depend on the 
quality of the displayed image.  Image display in many digital systems is a flexible and dynamic 
process whereby radiologists directly interact with the soft-copy image, which is displayed on a 
computer workstation.  The hardware component of a display system usually is composed of a 
display device and a display driver or graphics card.  The specifications given for a system are 
valid only for that particular combination of devices.  Another important aspect of the display 
  17  Contains Nonbinding Recommendations 
system is the hardware and software components used for maintaining the display presentation 
mapping between image values and luminance levels under a desired calibration model.  
Information regarding the calibration hardware, software, and procedures, including frequency 
and nature of the performed tests, should be identified in the charter and referenced as 
appropriate to a standard operation manual.  
 
  Selection of images for interpretation, display sequence, and randomization.  The 
charter should identify the nature and extent of images to be interpreted (e.g., all 
scheduled images, off-protocol images) and any important sequence aspects (e.g., 
baseline images followed by subsequent time point images).  The appropriateness of 
excluding images or portions of images from the interpretation (read) process should be 
emphasized and justified.  The charter should prespecify the following: 
 
  Criteria for classifying an image as uninterpretable based on a technical failure or 
other considerations that lead to the exclusion of an image from the interpretation 
process  
 
  Qualifications of an individual or individuals who are to make the determination of 
whether an image is included or excluded in the reading queue  
 
  Determination of and criteria needed to determine whether image readers can also 
decide if an image is uninterpretable when an individual or individuals other than the 
actual image readers have the responsibility of excluding certain images from the 
interpretation process 
 
  Criteria for how uninterpretable or missing imaging data will be accounted for 
(imputation scheme) in the data analyses 
 
  Potential for reader interpretation drift (i.e., deviation from study-specific image 
interpretation criteria on which readers have been trained) if images are assessed on 
an ongoing basis for a trial that includes multiple images obtained over time 
 
The process of randomized image presentation is often a key component of the overall 
image presentation plan.  If images (or image sets for a subject at any specific time point) 
are to be randomized for display to readers, the charter should describe the randomization 
process.  For each type of image presentation, the charter should describe the data locks 
(i.e., procedures that prevent modification of a readers final interpretation) to be used at 
the subject image set level.  These locks generally are critical to evaluating the 
contribution of each image examination to the overall assessment of a subjects image 
set.  The following are some examples of a trials image presentation process: 
 
  In a time-sequential presentation, a subjects complete image set (from baseline 
through the follow-up evaluations) is shown in the order in which the images were 
obtained.  In this process (unless prespecified and justified in the charter), the reader 
does not initially know the total number of time points in each subjects image set.  
 
  18  Contains Nonbinding Recommendations 
  In the simultaneous image presentation, a subjects complete image set is displayed 
(there is no blinding of date, sequence, or total number of images). 
 
  In the simultaneous, randomized temporal image presentation, a subjects complete 
image set is shown at the same time in a random order with respect to the date (there 
is no blinding to total number of images). 
 
  In the simultaneous time point presentation, a subjects single time point image set is 
randomized among many other subjects image sets.   
 
  In a hybrid, randomized image presentation, a subjects complete image set (or only 
the postbaseline images) is shown fully randomized.  After the read results have been 
locked for each time point, the images are shown again in known chronological order 
for reread.  Changes in any of the randomized assessments are tracked and 
highlighted in the final assessment.  In within-subject-control trials (e.g., comparative 
imaging), images obtained before and after use of the investigational drug should be 
presented in fully randomized unpaired fashion and in randomized paired fashion in 
two separate image evaluations.  The minimum number of images in each 
randomized block necessary to minimize recall should be considered.  
 
  Readers and their background qualifications.  When developing the charter, sponsors 
should identify the number of image readers and their requisite background 
qualifications.  The charter developers should consider the following: 
 
  The extent of technical knowledge essential to image interpretation. 
 
  The avoidance of any other reader involvement in the clinical trial (e.g., participation 
as an investigator) that might bias the interpretation of the images.1 
 
  The importance of confidentiality of image reads and/or the reading process. 
 
  The potential for reader fatigue and the use of substitute readers.  Decline in the 
quality of image interpretation caused by reader fatigue has been reported in clinical 
medicine (Krupinski, Berbaum, et al. 2012).2 
 
                                                 
1 Sponsors should also determine whether image readers should be considered to be clinical investigators.  Under 
the applicable regulations (21 CFR parts 54, 312, 314, 320, 330, 601, 807, 812, 814, and 860), a sponsor is required 
to submit to the FDA a list of clinical investigators who conducted covered clinical trials and to certify and/or 
disclose certain financial arrangements.  Additional information is available in the guidance for clinical 
investigators, industry, and FDA staff Financial Disclosure by Clinical Investigators.  We update guidances 
periodically.  To make sure you have the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
2 Similarly, in clinical trials, reader performance may be compromised if the readers are assigned an excessive 
number of images to examine within a short period of time.  The charter developers should consider whether to 
specify a maximum number of images to be read in a session if reader fatigue is an important consideration for 
image interpretation. 
  19  Contains Nonbinding Recommendations 
  The time commitment of readers and reader availability. 
 
  Any unique considerations for identification of a reader that adjudicates discordance 
in image interpretation between readers and that determines the final assessment. 
 
  The importance, if any, of clinical readers (i.e., image interpretation by clinicians 
aware of nonimaging clinical trial information). 
 
  Reader training and qualification.  The reader training process should be described, 
emphasizing the training documentation process and the use of any specific training 
materials (e.g., a training manual, training images), image display training sessions, and 
image read testing process.  The origin (e.g., other clinical trials) of training images 
should be described.  In addition, the charter should prespecify whether any performance 
criteria will be used to qualify readers after training and during the course of the trial.  
Reader training manuals are key documents that contain more details of the reader 
training procedures and should be provided for FDA review. 
 
Sponsors should consider the importance of the following items in the development of 
the reader training process: 
 
  An overview of the major goals of the image interpretation.  In general, reader 
training should emphasize only the image-specific aspects of the image interpretation 
process unless the process also integrates the use of clinical information.  The process 
should also minimize the potential for introduction of bias into image interpretation 
through knowledge of any potential image signatures that may break the desired 
blind-to-treatment assignment (e.g., if a PET ligand uptake is more common among 
the elderly, the coregistration of PET-computed tomography may bias the PET 
assessment because of recognition of aging-related cerebral atrophy on the 
tomogram). 
 
  An overview of the major expectations for image manipulation, lesion measurement, 
and other image evaluations.  Readers may benefit from special training in computer-
assisted interpretation, measurement, or other analysis tools as well as in the process 
for performing and recording measurements, especially if this process involves 
unique software data lock features and password-protected features.  The reading 
process may assume knowledge of unique assessment tools, such as Response 
Evaluation Criteria in Solid Tumors (RECIST) outcome expectations (Eisenhauer, 
Therasse, et al. 2009).  The charter should describe these expectations in detail and 
address situations when images may not be conducive to the requisite lesion 
measurement or other tool expectations. 
 
  Identification of any unique read definitions and/or criteria, including the use of 
image case report forms.  Some clinical trials may benefit from predefined criteria for 
reads (e.g., identification of the specific basis for an unreadable image), and these 
criteria may differ from commonly used clinical criteria.  Training and verification of 
  20  Contains Nonbinding Recommendations 
training (with mock image reads) may be important in documenting reader 
proficiency. 
 
  Description of any reader retraining procedures.  Some image interpretation 
processes may include the use of test images intermixed among the clinical trial 
images such that readers are intermittently tested as to the proficiency and/or 
consistency in their reads.  Failure to sustain proficiency may result in replacement of 
a reader with another trained and qualified reader.  The charter should describe the 
reader testing and retraining or replacement procedure. 
 
  Timing of image reads and the read process.  The charter should describe the timing of 
image reads with respect to the clinical trial conduct.  In some situations, prompt 
interpretation of images is important (e.g., for determining trial eligibility, confirming 
disease progression in trial subjects).  In other situations, images are interpreted only 
following completion of all subject evaluations.  Perhaps most commonly, readers can 
interpret images in batches periodically during the trial.  If readers interpret images in 
batches, the size of the batches should be specified, and the batch size should be justified 
to minimize recall bias.  The allowable time interval between the batch sessions also 
should be predefined.   
 
The charter should provide a detailed description of the image review process.  We 
recommend that the following be identified: 
 
  The review setting.   
 
  Whether readers interpret images independent of any other individuals.  Other 
individuals who may be present during the read should be specified and their roles in 
image interpretation described.  Any consensus read process should be detailed. 
 
  A description of any image adjudication process. 
 
  A detailed description of the use of any clinical information in the read.  
 
  A description of the read outcome information, to be included in case report forms, 
and any special procedures in this process (e.g., an initial read followed by a redisplay 
of images to form a global reassessment). 
 
  The assessment tools to be used and qualitative and/or quantitative measurements to 
be performed during the image read (e.g., modified RECIST criteria assessment of 
each image set). 
 
  A description of any computer software or other electronic processes involved in 
image interpretation, such as an automatic calculation of progression. 
 
  21  Contains Nonbinding Recommendations 
  Any lesion tracking system (e.g., certain requisite target lesions), particularly any 
nuances related to the appearance of new lesions for tracking, or inability to identify 
any previously tracked lesions (e.g., imaging problems, lesion resolution). 
 
  The options and/or requirements for image manipulation, including application of 
calipers, zoom, pan, adjustment of window/level, contrast inversion, and application 
of image enhancement features. 
 
  A description of any process for reread of images.  For example, a reader may 
experience a sudden illness that results in an incomplete image interpretation.  A 
prespecified plan for the rereading of incompletely read images helps to verify the 
integrity of the read process. 
 
  The readers role in citation of missing images or technical deficiencies within the 
images.  
 
  A description of the plan to ensure that all original read outcome information is 
locked and available for subsequent verification and comparison to any reread 
outcomes. 
 
When developing the image display process, sponsors should consider, as appropriate for 
the chosen modality, the key performance characteristics of medical displays such as 
luminance range; contrast ratio; reflection coefficients; grayscale; spatial, temporal (for 
image stacks), and color resolution; and spatial and temporal noise.  The charter should 
specify these details as well as other modality-specific items, such as the process for 
displaying dynamic images in relation to static images and any software manipulation of 
images for the minimization of degradations that may occur along the imaging process or 
transfer chain.   
 
Computer-assisted image interpretation may form an important component of the read 
process.  In general, the extent of computer assistance should be described explicitly 
within the charter, including a plan for quality control checks upon any critical software 
functions.  For example, the image interpretation may be driven primarily by a reader 
who uses a computer-assisted analysis tool to complement the readers initial assessment.  
Such reliance on computer assistance can be algorithmic (with prespecified parameters 
for the use of a tool) or can be elective.  In either case, such use should be defined within 
the charter in a manner that results in a sufficient audit trail and assessment of the roles of 
reader and reading tool.  To evaluate for systematic errors, we suggest that a subset of 
computer-generated analyses be verified by blinded external readers. 
 
If interpretation tools are to be used, the charter should specify the use of computer-
assisted interpretation tools that FDA has authorized for marketing.  Alternatively, an 
investigational interpretation tool justified for use with a given imaging modality can be 
used in some situations if the tool is compliant with all applicable FDA regulations, 
including the investigational device exemption requirements under 21 CFR part 812.  
Charter developers should review information regarding the software development 
  22  Contains Nonbinding Recommendations 
process and testing for investigational interpretation tools.  The same computer-assisted 
interpretation tool should be available to all readers at a site or centralized facility.  
 
  Imaging case report forms.  We anticipate that specific imaging interpretation case 
report forms could be important for many clinical trials, particularly trials that involve 
quantitative imaging within endpoint construction.  The charter should briefly describe 
the content of the case report form and emphasize the specific data content or notations 
that will be subsequently transferred to the sponsor to form the imaging database for the 
trials endpoint analyses.  We encourage the attachment of a case report form example to 
the charter.  On this case report form, sponsors should denote the specific items to be 
transferred to the sponsor to form the imaging analytical database.  In some situations, the 
case report form may consist of a tabular display of numbers (such as lesion 
measurements) or categories (such as predefined categories of bone erosion).  An 
example of the tabular display within the charter may help lessen the potential for errors 
during the imaging flow process. 
 
  Imaging data lock process.  At a predetermined point during the image review process, 
the image interpretation data (case report form information and any other important 
reader notations, including notations on images) generated by the readers should be 
locked.  Locking data means that no further modification of image assessment is allowed.  
The data locking process and timing should be closely linked with the image read 
process.  Data can be automatically locked by the imaging display equipment or triggered 
in response to reader notations.  In some situations, the reading process may include a 
reread of previously interpreted images, including access to locked data.  In all situations, 
the charter should describe the locking of data and any potential rereads.   
 
We encourage the use of an image lock approach to the read process whereby readers 
interpret the assigned image (or image set) and lock their reads (e.g., lesion 
measurements, response category, lesion severity) such that the contribution of each 
image read to the read outcome in each image set is documented and not altered.   
 
  Quality control of the image display and interpretation process.  The charter should 
describe the process for monitoring compliance with the image display and interpretation 
process.  This monitoring should include technical assessment of equipment, such as 
display systems and data locking software, as well as the reader interpretation process. 
 
Digital test patterns for quality control purposes can be used on a daily basis to ensure 
consistent performance and to detect changes in the hardware or software that can 
degrade image quality.  In some instances, automatic luminance corrections might 
compensate for the reduction in luminance that is expected over time.  Some of these 
quality control approaches offer the convenience of centralized reporting that facilitates 
the comparison of different display systems used in a given trial.  In some circumstances, 
these automatic adjustment features may actually complicate measurements if the 
features are unaccounted for.  In either case, information about such automatic 
compensation should be known and accounted for. 
 
  23  Contains Nonbinding Recommendations 
In some clinical trials, evaluation of reader interpretation performance will be of value to 
help assess the extent to which readers are consistent in image interpretation and comply 
with the trial specifications.  We recommend evaluating intra- and inter-reader 
performance with defined and prespecified metrics based upon evaluations that are 
ongoing during the image interpretation process.  
 
In many situations, intra-reader variability as a measure of reader performance should be 
assessed by periodic blinded testing of the reader with a preselected or predefined set of 
images interspersed with the clinical trial images.  These reader testing images can come 
from a source external to the trial or, with proper data locking methods, from 
reinterpretation of selected clinical trial images.  If clinical trial images will be used as 
reader testing images, then prespecified methodology should ensure that the original 
image interpretation is considered final and, for intra-reader variability, that a sufficient 
period occurred between the reading and rereading of the images to minimize recall bias.  
A change in reader performance is not infrequently observed in clinical trials, and 
depending upon the role of imaging in the trial, periodic reader retraining and 
requalification may be critical.  All details of reader testing, retraining, requalification, 
and possible replacement should be prespecified within the charter and/or supporting trial 
documents.  
 
Image interpretation is inherently subjective, and readers of the same image may 
justifiably disagree in their interpretations of the image.  In these situations, a strategy for 
reconciliation of discordant image interpretation to provide a final image outcome should 
be detailed in the charter.  
 
In some situations, the frequency of the reader adjudication may provide a sense of the 
inherent subjectivity within the image outcome.  Knowledge of the adjudication rate may 
be important for interpreting the results.  When developing clinical trial protocols and the 
charter/supporting documents, the trial developers should consider the potential effect of 
reader interpretation variability upon the clinical trial outcomes, and if the image 
adjudication rate is regarded as an important consideration, then the trial documents 
(protocol and statistical analysis plan) should prespecify this rate determination process.   
 
Charter Modifications Before Imaging 
 
The charter should briefly describe the process for modifying the charter in response to potential 
deficiencies within the imaging process or in response to a need to improve the process.  
Sponsors should describe the plan for submitting charter modifications to the FDA and other 
regulatory authorities.  In general, we anticipate charter revisions to be uncommon, particularly if 
imaging has been used in exploratory clinical trials and the imaging processes follow precedents.  
To assess the sufficiency of the imaging plans for a phase 3 trial, sponsors can conduct pilot 
reading studies to test the reading and image lock process, the report form, and other important 
aspects of imaging.  If so, these pilot studies should not involve images or data that will be used 
in the phase 3 trial. 
 
  24  Contains Nonbinding Recommendations 
Imaging Data Transfer Process to the Sponsor 
 
Image interpretation should result in the completion of a case report form and/or tabular display 
of numbers, measures, or categories of responses.  The charter should describe the process for 
transfer of this information to the sponsor and the time point or points for transmission of this 
information.  The charter should describe how the sponsor will use the transferred information to 
establish the variables used in the analysis of the primary endpoint. 
 
Archiving of Images and Image Interpretations 
 
Images should be archived as a usual component of subject care as well as for use as the source 
documentation in clinical trials.  Electronic source data should meet the same elements of data 
quality that are expected of paper records and should comply with all applicable statutory and 
regulatory requirements.  The FDAs acceptance of data from clinical trials for decision-making 
purposes relies upon verification of the quality and integrity of data, generally based upon the 
findings from audits and inspections.3  In addition to images themselves, the image 
interpretations (case report forms or assessment tabulations) represent source data and should be 
retained for potential inspection and auditing.  All required source records, whether electronic or 
paper, must be retained for a period of no less than 2 years following approval of a marketing 
application or discontinuation of shipment and delivery of the drug for investigational use, as 
described in 21 CFR 312.57(c) and 21 CFR 312.62(c).   
 
The charter should describe the process for archiving imaging information by the site 
investigator as well as by the sponsor.  In some situations, the sponsor may choose to archive the 
imaging at a centralized contractual facility or institution.  Regardless of the physical storage 
route, the archiving process should address the following items: 
 
  Limiting access to ensure images and data are retained in their original forms 
  Providing back-up storage 
  Archiving in a manner conducive to a clear audit trail, including date and time stamps 
 
Additional information regarding systems and personnel controls for computerized source data is 
described in the guidance for industry Computerized Systems Used in Clinical Investigations. 
 
Verification of Fidelity of Charter Documents With the Clinical Protocol and Statistical 
Analysis Plan 
 
Because the charter may consist of an ensemble of technical documents, the developers of the 
charter should include a final step in which all the documents are reviewed to ensure that the 
charters technical specifications do not contradict or modify the protocol-specified imaging 
endpoints.  Many individuals and organizations may be involved in the development of a charter.  
These entities may offer perspectives and proposals that may be thought to enhance or 
functionally adapt technical specifications in response to clinical protocol imaging expectations.  
These alterations and interpretations may, in fact, redefine important trial endpoints via the 
                                                 
3 See the guidance for industry Computerized Systems Used in Clinical Investigations. 
  25  Contains Nonbinding Recommendations 
proposed imaging technical details.  We encourage sponsors to include in their charters a brief 
section that states all imaging technical documents will be reviewed to ensure that the imaging-
specific details produce imaging outcomes consistent with the trials clinical protocol and 
statistical analysis plan. 
 
  26  Contains Nonbinding Recommendations 
APPENDIX B:  
DURING IMAGING:  MONITORING PLANS AND CHARTER MODIFICATIONS 
 
A plan for ongoing monitoring of the imaging process is critical to ensure the quality of the 
acquired images.  Revisions to the imaging procedures might be recommended if unanticipated 
technical issues arise.   
 
Monitoring Plans 
 
The charter should outline the complete plan for monitoring the imaging process.  The extent of 
monitoring is anticipated to vary widely, dependent upon the use of imaging within a trial.  In 
some situations, monitoring will be minimal; in other trials, intense monitoring (to include 
requalification of equipment with phantoms and periodic retesting of readers) will be critical.  
Sponsors should comply with the monitoring plan described within the charter.  Verification of 
this compliance may prove an important component of the assessment of imaging data integrity.   
 
Charter Modifications 
 
During the clinical trial, circumstances may prompt modification of the imaging procedures.  For 
example, unanticipated technical features may obscure a portion of an image or preclude one of 
the expected quantitative assessments.  In these situations, we recommend that the sponsor revise 
the charter to correct the problem and maintain a record of the modification.  The revision should 
identify any potential effect of the modification upon the trials important endpoint analyses.  In 
some situations, modification of the charter may affect the definition of the primary endpoint 
(e.g., alteration of the method for lesion measurement may call into question the clinical 
meaningfulness of any size changes) and result in reconsideration of the role of imaging in the 
trial or premature termination of the trial.  To avoid these difficulties, we encourage sponsors to 
thoroughly consider the role of imaging (including the technical aspects) in a clinical trial, 
especially if the imaging is highly technical and/or relies upon quantitative assessments that 
require vigilant subject and site cooperation with the imaging process.  The use of imaging in 
early phases of drug development may help lessen the challenges associated with wider use of 
the technology in trials intended to support a drugs approval. 
 
 
  27  Contains Nonbinding Recommendations 
APPENDIX C:  
AFTER IMAGING:  DATA TRANSFER, ARCHIVING, AND 
ANALYSIS OF IMAGING INFORMATION 
 
A description of the procedures for the transfer of imaging data (e.g., from a trial site to a 
centralized facility for image interpretation, from a centralized facility to a sponsor for analysis) 
is critical for verification of data quality and integrity. 
 
Data Transfer 
 
It is important for sponsors to document fidelity to the charter-specified process of imaging 
information transfer from a site to a centralized facility and from the centralized facility to the 
sponsor throughout the clinical trial.  Many clinical trials are likely to involve transfer of imaging 
data to the sponsor only following completion of all image assessments and interpretations, and 
some may involve image annotations before this transfer (such as a documented caliper-based 
lesion measurement).  In these situations, documentation of image and imaging information 
transfer may greatly facilitate the completion of audits of the clinical trials imaging procedures. 
 
Archiving 
 
Sponsors and investigators should comply with the charter-specified plan for imaging source 
data archiving.  Deviations from this plan and/or loss of imaging information may compromise 
the ability of the FDA to verify data quality and/or prompt reassessment of images.  We do not 
accept images as a component of new drug applications or biologics license applications.  
However, we may request that sponsors display images, as part of records and reports relating to 
a clinical investigation; upon our request, sponsors must permit the FDA to have access to these 
records (see 21 CFR 312.58(a)).  
 
Analysis of Image Information 
 
We anticipate that most analyses of imaging information will be performed by the sponsor (or 
the sponsors designated analysts) in accordance with the clinical protocol specifications.  In 
some situations, clinical sites or a centralized facility may analyze certain aspects of imaging as a 
quality control measure (such as the determination of reader interpretation consistency).  
Sponsors should specify these site and centralized facility roles in the charter.  Clinical trial 
imaging data should not be analyzed in an ad hoc, unplanned manner. 
 
Imaging processes that took place during the conduct of the trial (such as image acquisition, 
image interpretation, data transfer, and other processes described in the guidance) should be 
thoroughly presented in the final report submitted for FDA review. 
 
  28