A Feature Comparison Study to Evaluate the Modified Processing of Fujifilm's ASPIRE Cristalle With Digital Breast Tomosynthesis Option as Compared to the Original Processing
Conditions: Breast Cancer
Sponsor: Fujifilm Medical Systems USA, Inc.

FUJIFILM Medical Systems U.S.A., Inc. 
Protocol FMSU2017-003 
 
 
 
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A Feature Comparison Study to  
Evaluate the Modified Processing of  
Fujifilm’s ASPIRE Cristalle with  
Digital Breast Tomosynthesis Option as  
Compared to the Original Processing 
 
 
 
 
 
 
 
 
 
FUJIFILM Medical Systems U.S.A., Inc. 
419 West Avenue 
Stamford, Connecticut 06902 
 
 
 
 
 
 
 
 
 
This document contains proprietary and confidential information of FUJIFILM Medical Systems U.S.A., 
Inc. (Fujifilm). Acceptance of this document constitutes agreement by the recipient that no unpublished 
information contained herein will be published or disclosed without prior written authorization from Fujifilm 
except that this document may be disclosed to study personnel under your supervision who need to know 
the contents for conducting the study and appropriate Institutional Review Boards under the condition that 
they are requested to keep it confidential. The foregoing shall not apply to disclosure required by 
governmental regulations or laws; however, Fujifilm must be promptly informed of any such disclosure. 
 
 
 

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Table of Contents 
 
Abbreviations ............................................................................................................................ 4 
Definitions ................................................................................................................................. 6 
Tables and Figures ................................................................................................................... 8 
1. 
Sponsor Protocol Approval Signature Page .................................................................... 9 
2. 
Investigator Agreement Signature Page......................................................................... 10 
3. 
Protocol Synopsis ............................................................................................................ 11 
4. 
Fujifilm FMSU2013/2017 Applicable Series Protocols ................................................... 14 
5. 
Investigators and Study Administrative Structure ........................................................ 15 
6. 
Background and Rationale .............................................................................................. 16 
7. 
Investigational Plan ......................................................................................................... 17 
7.1. 
Purpose ..................................................................................................................... 17 
7.2. 
Study Objectives ....................................................................................................... 17 
7.3. 
Feature Comparison Study Population ................................................................... 17 
7.3.1. 
Sample Size and Case Mix .................................................................................. 17 
7.3.2. 
Inclusion and Exclusion Criteria ........................................................................... 18 
7.3.3. 
Case Selection and Targeted Distribution ............................................................ 18 
7.4  
Risk/Benefit Assessment ......................................................................................... 19 
8. 
Reader Selection and Training ........................................................................................ 20 
8.1. 
Purpose ..................................................................................................................... 20 
8.2. 
Selection and Qualification Criteria for Readers .................................................... 20 
8.3. 
Conduct of the Training Process ............................................................................. 20 
8.4     Conduct of the Reading Process .............................................................................. 20 
8.4.1 
    Purpose and Conduct ....................................................................................... 20 
8.4.2 
Core Reading Center ........................................................................................... 22 
8.4.3   Preparation of Cases for Interpretation .................................................................... 22 
8.4.4 
Workflow for the Interpretation of Cases .............................................................. 22 
9. 
Statistical Analysis .......................................................................................................... 23 
9.1. 
Analysis Set .............................................................................................................. 23 
9.2 
Analysis of Primary Objective .................................................................................. 23 
9.3 
Sample Size Justification ......................................................................................... 23 
10. Sponsor and Investigational Site Requirements (Study Administration) ..................... 24 
10.1 
Ethics ......................................................................................................................... 24 
10.1.1 
Ethical Conduct of the Study ................................................................................ 24 
10.1.2 
Institutional Review Board.................................................................................... 24 
10.2 
Reader Informed Consent ........................................................................................ 26 
10.3 
Protocol Compliance ................................................................................................ 26 
10.3.1 
Protocol Amendments .......................................................................................... 26 

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10.4 
Retention of Study Records ..................................................................................... 26 
10.5 
Data Collection and Management ............................................................................ 27 
10.5.1 
General ................................................................................................................ 27 
10.5.2 
Data Management Center .................................................................................... 27 
10.6 
Confidentiality ........................................................................................................... 27 
10.6.1 
Subject Confidentiality ......................................................................................... 27 
10.6.2 
Reader Confidentiality .......................................................................................... 27 
10.6.3 
Transfer of Confidential Information to the Sponsor or the DMC .......................... 28 
10.7 
Study Monitoring ...................................................................................................... 28 
10.8 
Sponsor Audits ......................................................................................................... 28 
10.9 
Inspection by a Regulatory Agency ......................................................................... 28 
10.10 
Financial Disclosure.............................................................................................. 28 
10.11 
Study or Study-site Termination .......................................................................... 29 
11 Appendices....................................................................................................................... 30 
Appendix A: Fujifilm FFDM and DBT Image Acquisition and Display ............................. 30 
Appendix B: Inclusion and Exclusion Criteria from FMSU2013-004A ............................. 31 
Inclusion Criteria ................................................................................................................ 31 
Exclusion Criteria ............................................................................................................... 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abbreviations 
Abbreviation 
Explanation 
ACR® 
American College of Radiology 
BI-RADS® 
Breast Imaging Reporting and Data System 
CC 
Cranio-Caudal 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DBT 
Digital Breast Tomosynthesis 
DCF 
Data Clarification Form 
DMC 
Data Management Center 
DVIIm 
Dynamic Visualization for Mammography 
EDR 
Exposure Data Recognizer  
EDR2m 
Exposure Data Recognizer 2 for Mammography 
FBP 
Filtered Back Projection 
FDA 
Food and Drug Administration 
FFDM 
Full-Field Digital Mammography (also known as Digital Mammography) 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
ID 
Identification 
IRB 
Institutional Review Board 
ISR 
Iterative Super-Resolution Reconstruction 
LCC 
Left Cranio-Caudal 
LMLO 
Left Medio-Lateral Oblique 
MFP 
Multi-Objective Frequency Processing 
MFP2 
Multi-Objective Frequency Processing 2 
MLO 
Medio-Lateral Oblique 
MQSA 
Mammography Quality Standards Act 

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PHI 
Protected Health Information 
PMA 
Premarketing Approval Application 
RCC 
Right Cranio-Caudal 
RMLO 
Right Medio-Lateral Oblique 
 
 

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Definitions 
 
ACR® BI-RADS® 
Breast Tissue 
Composition 
(Density) Categories 
a. The breasts are almost entirely fatty 
b. There are scattered areas of fibroglandular density 
c. The breasts are heterogeneously dense, which may obscure small masses 
d. The breasts are extremely dense, which lowers the sensitivity of mammography 
ACR® BI-RADS® 
Assessment 
Categories 
Assigned by reader;  
0 = Incomplete -  Need Additional Imaging Evaluation and/or Prior Mammograms for 
Comparison 
1 = Negative 
2 = Benign  
3 = Probably Benign. Management: Short-interval (6-month) follow-up or continued 
surveillance mammography 
4 = Suspicious. Management: Tissue diagnosis. 
4A = Low suspicion for malignancy 
4B = Moderate suspicion for malignancy 
4C = High suspicion for malignancy 
5 = Highly Suggestive of Malignancy 
ASPIRE Bellus II 
Fujifilm mammography viewer (see Appendix A) where the FFDM and DBT images are 
displayed and reviewed by the physician. 
ASPIRE Cristalle 
with DBT Option 
Fujifilm’s Mammography Acquisition System (see Appendix A) which generates both 
FFDM and DBT images. 
Benign Case 
A case in which all lesions are confirmed as benign by a biopsy or surgery and no other 
lesions are biopsy-malignant. 
Cancer Case 
A case in which at least one lesion is confirmed as malignant by biopsy or surgery. 
Case 
Two views (CC and MLO) of one breast.  
DBT Examination 
Each DBT Examination has two parts: 
 
Acquisition: Acquisition of DBT images for each of the standard bilateral CC and 
MLO views (RCC, LCC, RMLO, LMLO) using the ASPIRE Cristalle. 
 
Review: DBT images are displayed and interpreted by the physician on the ASPIRE 
Bellus II. 
DBT Images 
A series of mammograms, which are reconstructed from multiple low-dose projection 
images captured by the ASPIRE Cristalle with the x-ray tube rotated at a number of small 
offset angles over a limited angular range while the breast remains compressed and 
unmoved.  
DBT Read 
The physician reads (interprets) the DBT images displayed on the ASPIRE Bellus II (see 
Appendix A) 
DBT Views 
A series of cross-sectional views of the DBT images for each of the CC and MLO views 
for each breast.  

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Evaluable Subject  
Based on acquisition-site data, an evaluable subject is a subject with known true clinical 
status and with complete DBT and FFDM examinations (four standard views), in which 
there is sufficient anatomical coverage, sufficient contrast, no significant motion or other 
artifacts, limited noise, and similar positioning. 
FMSU2013-004A 
Acquisition of Digital Mammography and Breast Tomosynthesis Images for Clinical 
Evaluation of Fujifilm Digital Breast Tomosynthesis 
FMSU2017-003 
A Feature Comparison Study to Evaluate the Modified Processing of Fujifilm’s ASPIRE 
Cristalle with Digital Breast Tomosynthesis Option as Compared to the Original 
Processing 
Fujifilm 
FUJIFILM Medical Systems, U.S.A., Inc.  
IA Site DBT Reader 
An image-acquisition site reader is an MQSA-qualified radiologist who interprets the DBT 
images at the time of image acquisition (see FMSU2013-004A). 
Image Set 
One (1) image with Original Processing, and one (1) image with Modified Processing of 
two views (CC and MLO) of the same breast.  
Modified Processing 
Fujifilm’s ASPIRE Cristalle with Digital Breast Tomosynthesis Option with a) iterative 
super-resolution reconstruction (ISR) and b) Dynamic Visualization II for Mammography 
(DVIIm = EDR2m + MFP2) presentation processing.  
Negative Case 
A negative case is defined as a case where there are no abnormal areas or malignant 
(cancer) findings within a year (within 320 to 455 days) from the original screening 
examination.  
Non-Cancer Case 
A biopsy benign case, or a recall case, or a normal case. 
Original Processing 
Fujifilm’s ASPIRE Cristalle with Digital Breast Tomosynthesis Option with FDA-approved 
filtered back projection (FBP) with EDR and MFP presentation processing. 
Prior Mammogram  
Historical mammogram acquired on any media – including screen-film, digitized image, 
FFDM and/or DBT. 
Recall Case 
A case where there is a suspicious area(s) identified in the screening exam that needs 
additional work‐up to determine if the area is cancerous or not.  This is determined at the 
IA site. 
Standard views 
Standard CC and MLO views for each breast (RCC, LCC, RMLO, LMLO). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Tables and Figures 
 
Table 1. Image Acquisition Sites and Principal Investigators .....................................................17 
Table 2. Sampling Plan .............................................................................................................19 
Table 3. Mammographic Features to be Graded .......................................................................21 
Table 4. Number of Subjects Needed Per Reader for Tests of Non-inferiority ...........................24 
 
 
Figure A. ASPIRE Cristalle DBT Option - Fujifilm’s mammography acquisition system. ............30 
Figure B. ASPIRE Bellus II - Fujifilm’s mammography viewer. ..................................................30 
  

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1. Sponsor Protocol Approval Signature Page 
Study Title 
A Feature Comparison Study to Evaluate the Modified 
Processing 
Tomosynthesis Option as Compared to the Original Processing 
Protocol Number 
FMSU2017-003 
Effective Date  
May 8, 2018 
Study Sponsor 
FUJIFILM Medical Systems U.S.A., Inc. 
419 West Avenue 
Stamford, Connecticut 06902 
 
 
 
 
 
 
 
 
 
 
 
 
 
FUJIFILM Medical Systems U.S.A., Inc. 
Approval 
Name, Title 
 
Signature 
 
Date 
 
 
 
 

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3. 
Protocol Synopsis 
SPONSOR NAME 
FUJIFILM Medical Systems U.S.A., Inc. 
PROTOCOL NUMBER 
FMSU2017-003 
STUDY TITLE 
A Feature Comparison Study to Evaluate the Modified Processing of Fujifilm’s 
ASPIRE Cristalle with Digital Breast Tomosynthesis Option as Compared to the 
Original Processing 
DEVICE NAME 
Fujifilm ASPIRE Cristalle with DBT Option Utilizing ISR and DVIIm 
PURPOSE 
The purpose of the feature comparison study is to evaluate general mammographic 
features in images of the same breast when reconstructed with modified (ISR and 
DVIIm) processing as compared to the original processing (FBP with EDR and MFP).   
One breast per subject (two views per breast) will be assessed by approximately six 
(6) readers.  
STUDY OBJECTIVES 
 
The following primary objectives will be tested simultaneously, and include: 
 
 
Non-inferiority in each of 7 general mammographic features of the 
modified processing  
CORE READING CENTER 
The feature comparison study will be performed at International HealthCare, LLC in 
Norwalk, CT.  
PRINCIPAL INVESTIGATOR 
AND READERS 
The principal investigator for this study is Laurie Fajardo, MD, MBA, FACR, FSBI. 
The feature comparison study radiologist readers shall meet all criteria for their 
respective roles as specified in the investigational plan.  
The feature comparison study readers will participate in a training session to ensure 
their understanding of the ASPIRE Bellus II workstation, the protocol, the study CRFs, 
study processes, GCP, and their obligations as study participants. 
 

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FEATURE COMPARISON 
STUDY DESIGN 
 
 
Six MQSA-qualified and board-certified mammographers representing various 
experience levels, will be shown DBT images of a breast with the modified processing 
side-by-side the same breast with the original processing.  One breast per subject 
(two views per breast; CC and MLO) will be evaluated by the readers. Readers will be 
blinded to the image reconstruction and presentation processing methods.  Each 
reader will be given a different sample of cases to review. Approximately 600 total 
cases (100 cases per reader) will compose the sample. The order of the subjects and 
location (left or right review workstation high resolution monitor) of the images with 
modified processing will be randomized for each reader. 
 
Readers will compare several general mammographic features.  Readers will be 
asked to grade each feature on each view (CC and MLO) using the following 5-point 
scale, with specific training to use the score=0 category sparingly: 
 
-2 
(left image much superior) 
-1 
(left image somewhat superior) 
0 
(left and right images are equivalent) 
+1 
(right image somewhat superior) 
+2 
(right image much superior) 
 
Interpretation instructions: The reader will complete the CRFs for each case for both 
CC and MLO views. The list of individual general mammographic features and lesion 
specific features are outlined below. Note that the results of the three lesion-specific 
features as well as diagnostic confidence (#8-11 below) will not be evaluated as part 
of this study.   
 
1. Exposure, assessing visualization of the adipose and fibroglandular tissues 
and visualization of breast tissue underlying the pectoralis muscle, separately;  
2. Breast composition, assessing overlapping breast structures, uniformity of 
exposure of fibroglandular tissues, adequacy of penetration of thicker portions 
of the breast, exposure of thinner areas and motion unsharpness; 
3. Image contrast for differentiation of subtle tissue density differences; 
permitting image contrast assessment adjustment of the window and level 
settings;  
4. Sharpness, assessing the edges of fine linear structures, tissue borders, and 
benign calcifications;  
5. Tissue visibility at the skin line;  
6. Noise, i.e., noise obscuring breast structures or suggestive of structures not 
actually present; 
7. Artifacts due to image processing, detector failure and other factors external 
to the breast on soft-copy displays; and 
 
8. Ability to characterize a Mass (when present) based on conspicuity, margin 
sharpness, shape;  
9. Ability to characterize Calcifications (when present) based on conspicuity, 
sharpness/shape, distribution;  
10. Ability to characterize an Architectural Distortion (when present) based on 
conspicuity, sharpness. 
11. Diagnostic confidence. 
 

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STUDY ANALYSIS 
 
The proportion of cases where the readers judged the modified image processing as 
non-inferior will be calculated.  Non-inferiority will be defined as a score of equivalence 
between modified and original or a score indicating the modified image processing is 
superior.  For each reader, the proportion of cases judged as non-inferior with 
modified processing will be calculated for each feature and each view.  A pooled 
estimate will also be calculated where the results over all readers and views will be 
combined.  95% percentile bootstrap CIs will be constructed for the pooled proportions 
of cases judged as non-inferior with the modified processing. These CIs will be 
reported for each feature. 
 
The primary objective is the readers’ assessment for each of the 7 general 
mammographic features.  The null hypothesis is that the pooled proportion of cases 
judged as non-inferior with modified image processing is <0.50, versus the alternative 
hypothesis that the pooled proportion is >0.50. If the 95% CI does not contain values 
<0.50, then the null hypothesis will be rejected. These hypotheses will be evaluated 
for each of the 7 general mammographic features.  If all 7 null hypotheses are 
rejected, then it will be concluded that the modified imaging features are non-inferior 
to the original imaging 
 
 
 

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4. Fujifilm FMSU2013/2017 Applicable Series Protocols 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fujifilm Protocol FMSU2013-004A 
Acquisition of Digital Mammography and Breast 
Tomosynthesis Images for Clinical Evaluation of Fujifilm 
Digital Breast Tomosynthesis 
Fujifilm Protocol FMSU2017-003 
A Feature Comparison Study to Evaluate the Modified 
Processing of Fujifilm’s ASPIRE Cristalle with Digital 
Breast Tomosynthesis Option as Compared to the Original 
Processing 
 

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5. Investigators and Study Administrative Structure 
Study Personnel: 
 
Principal investigator 
Laurie L. Fajardo, M.D., MBA, FACR, FSBI 
Radiology Consultant 
1730 Lucky John Dr. 
Park City, UT 84060 
Phone: 319.331.4297 
 
Sponsor 
FUJIFILM Medical Systems U.S.A., Inc. 
419 West Avenue 
Stamford, CT 06902 
Robert A. Uzenoff 
Executive Director, Clinical Science 
Phone: 203.602.3664 
Email: ruzenoff@fujifilm.com  
Nicole Calabrese, MS 
Contract Project Manager 
Phone: 518.506.9840 
Email: ncalabrese.contractor@fujifilm.com   
Statistician 
The Cleveland Clinic Foundation 
9500 Euclid Ave  
Quantitative Health Sciences /JJN3 
Cleveland, OH 44195-5196 
Nancy Obuchowski, PhD 
Phone: 216.445.9549 
Email: ObuchoN@ccf.org  
 
 

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6. Background and Rationale 
 
The following software changes have been made to the FDR-3000AWS of the PMA 
P160031 device; Dynamic Visualization II for mammography (DVIIm) and Iterative Super-
Resolution Reconstruction (ISR).  
 
DVIIm consists of EDR2 and MFP2, which are detailed as follows:   
 
 
Exposure Data Recognizer 2 for mammography (EDR2m) – the EDR2m algorithm 
analyzes image data and identifies various anatomic structures using a statistical 
estimation method as opposed to original EDR’s histogram analysis method. EDR2m 
determines the parameters to optimize brightness and contrast of the image based on 
the analysis result. 
 
Multi-Objective Frequency Processing 2 (MFP2) - MFP2 optimizes the brightness, 
contrast and sharpness of the image using parameters determined by the EDR2m 
processing. MFP2 uses additional low frequency tables and a combination of 
automatic and preset dynamic range control operations. 
 
Iterative Super-Resolution Reconstruction (ISR) is a new reconstruction algorithm that uses 
an iterative method to improve image quality including increased sharpness and lower 
noise. ISR applies super-resolution technology to improve the visibility of fine structures 
such as calcifications, and reduces the severity of artifacts. 
 
Note: ISR replaces filtered back projection (FBP), and DVIIm (EDR2m and MFP2) replaces 
EDR and MFP, the methods used in the original PMA P160031 device.   
 
 

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7. 
Investigational Plan 
7.1. 
Purpose 
The purpose of the feature comparison study is to evaluate general mammographic features 
of the same breast when reconstructed with modified (ISR and DVIIm) presentation 
processing as compared to the original processing (FBP with EDR and MFP).   
7.2. 
Study Objectives 
The primary objective is: 
 
Non-inferiority in each of the seven general mammographic features of the modified 
processing  
 
 
7.3. 
Feature Comparison Study Population 
Approximately 600 cases (breasts) will be selected from mammograms that were acquired 
under Fujifilm protocol FMSU2013-004A. Each of the six (6) readers will evaluate 100 
unique cases in randomized order. 
 
Table 1. Image Acquisition Sites and Principal Investigators 
Image-Acquisition Site 
Principal Investigator’s Name 
City, State 
Elizabeth Wende Breast Care, LLC 
Stamatia Destounis, MD 
Rochester, NY 
Scottsdale Medical Imaging, LLC 
Denise Reddy, MD 
Scottsdale, AZ 
University of Iowa Hospitals and 
Clinics 
Limin Yang, MD 
Iowa City, IA 
The University of North Carolina at 
Chapel Hill  
Cherie Kuzmiak, DO 
Chapel Hill, NC 
University of Texas San Antonio 
Pamela Otto, MD 
San Antonio, TX 
 
7.3.1. Sample Size and Case Mix 
Approximately 230 cancer cases and approximately 370 non-cancer cases will be 
selected by the statistician for this feature comparison reader study from the library of 
DBT mammograms collected under Fujifilm protocol FMSU2013-004A.  
The approximately 370 non-cancer cases will include:  
 
approximately 190 biopsy benign cases, 
 
approximately 60 recall cases, 
 
approximately 60 normal cases, and 

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 
approximately 60 cases lost to follow-up. 
7.3.2. Inclusion and Exclusion Criteria 
All cases for this feature comparison reader study will meet the following eligibility 
inclusion and exclusion criteria (see also Appendix B for complete inclusion and 
exclusion criteria from protocol FMSU2013-004A). Only subjects who were consented 
and met all inclusion criteria and none of the exclusion criteria were considered 
evaluable. 
 
 
      Inclusion Criteria 
 
Eligible subjects under protocol FMSU2013-004A, defined as female subjects 
with complete FFDM and DBT examinations, in which there is sufficient 
anatomical coverage, sufficient contrast, and no significant motion or other 
artifacts, as determined by the image-acquisition sites. 
 
Meet none of the exclusion criteria under protocol FMSU2013-004A. 
     Exclusion Criteria 
 
Subjects who are in violation of protocol FMSU2013-004A. 
 
Subjects who meet exclusion criteria under Fujifilm protocol FMSU2013-004A. 
 
7.3.3. Case selection and Targeted Distribution 
Cases will be randomly selected from Fujifilm’s existing library (collected under protocol 
FMSU2013-004A).  A stratified randomization is proposed where the strata and 
proposed sampling proportions are summarized in Table 2.  Within each stratum, cases 
will be randomly selected so that approximately 10% have extremely dense breasts, 
40% have heterogeneously dense breasts, 40% have scattered fibroglandular breasts, 
and 10% have fatty breasts.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 2. Sampling Plan 
 
Stratum, defined by 
Reference Standard* 
# available 
subjects 
Overall 
sample 
composition 
# cases per 
reader 
Total # cases 
Cancer: (N=229) 
  Architectural Distortion 
  Microcalcification 
  Asymmetry 
  Mass 
  Other 
 
21 
86 
19 
95 
8 
38% 
 
3-4 
14-15 
3-4 
15-16 
1-2 
 
21 
86 
19 
95 
8 
Biopsy Benign: (N=457) 
  Architectural Distortion 
  Microcalcification 
  Asymmetry 
  Mass 
  Other 
 
19 
212 
43 
158 
25 
32% 
 
3-4 
10 
7-8 
9 
2-3 
 
19 
60 
43 
54 
15 
Recalled/No Biopsy 
98 
10% 
10 
60 
Negative 
234 
10% 
10 
60 
Unknown 
209 
10% 
10 
60 
Total 
1227 
100% 
100 
600 
*There are 1031 biopsied lesions in 894 subjects available for selection for this study.  Because there are 
subjects with multiple lesions, cases in the table are organized first by the presence/absence of a 
malignant lesion, and then by presence/absence of an AD (and possibly another lesion), 
microcalcification, asymmetry, mass, and other, respectively.  There were 208 subjects with lesions but 
no definitive biopsy diagnosis, including 24 ADs, 24 microcalcifications, 75 asymmetries, and 49 masses.  
 
 
 
7.4  
Risk/Benefit Assessment 
 
The probable benefits of the software are based on the data that will be collected in the 
clinical study being conducted to support PMA supplement approval. 
 
The software has no significant risk of direct harm to the patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8. 
Reader Selection and Training 
8.1. 
Purpose 
The purpose of the training process is to ensure that each reader selected for the reading 
session has been adequately trained to evaluate the DBT image sets on the ASPIRE Bellus 
II workstation.   
8.2. 
Selection and Qualification Criteria for Readers 
This study will be conducted with radiologists of varying experience levels, from both 
community and academic practices. These radiologists were not associated with the 
acquisition or original clinical review of cases.  
Base qualification criteria: All readers must meet the following base criteria: 
 
Are board-certified  
 
Are MQSA-qualified for DBT interpretation 
 
8.3. 
Conduct of the Training Process 
 
Training will include review of the case report forms to ensure reader understanding of the 
mammographic features they will be evaluating images based on, as well as the 5-point 
scale they will be utilizing to grade each image set. Readers will be specifically instructed to 
use the score=0 sparingly. GCP will also be reviewed and documented via attestation form 
during the training process.  
 
Training will also consist of a hands-on session at the workstation to provide the readers 
with an overview of its pertinent DBT-specific functionality. 
 
Following the successful completion of the reader training, the readers will independently 
review and score each of the approximately 100 image sets at their own designated 
workstation. Interpretation of mammography images will be performed in a controlled 
environment with consistent lighting. The review workstations will be preloaded with the 
cases. The reading time allowed per image set will not be limited. A lunch break will be 
offered during the reading session, and radiologists will be encouraged to take a 5-10 
minute break each hour, as needed. Each reader will dictate their evaluations to a trained 
scribe, who will enter the dictation onto a paper CRF. Each reader will sign an attestation 
form verifying the documented information. 
              8.4     Conduct of the Reading Process 
8.4.1     Purpose and Conduct 
The purpose of the reading process is for the readers to evaluate, side-by-side, images of 
the same breast reconstructed with the modified and original processing methods. 

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Readers will compare several general mammographic features.  Readers will be asked to 
grade each feature on each view (CC and MLO) using the following 5-point scale:  
 
-2 (left image much superior) 
-1 (left image somewhat superior) 
 0 (left and right images are equivalent) 
+1 (right image somewhat superior) 
+2 (right image much superior) 
The list of individual general features and three lesion-specific features is given in Table 3.  
Note that the results of the three lesion-specific features as well as diagnostic confidence 
(#8-11 below) will not be evaluated as part of this study.  Readers will be specifically 
instructed to use the score=0 sparingly. 
 
Table 3. Mammographic Features to be Graded 
 
1. Exposure, assessing visualization of the adipose and fibroglandular tissues and 
visualization of breast tissue underlying the pectoralis muscle, separately; 
2. Breast compression, assessing overlapping breast structures, uniformity of exposure 
of fibroglandular tissues, adequacy of penetration of thicker portions of the breast, 
exposure of thinner areas, and motion unsharpness; 
3. Image contrast for differentiation of subtle tissue density differences; permitting image 
contrast assessment adjustment of the window and level settings.  
4. Sharpness, assessing the edges of fine linear structures, tissue borders, and benign 
calcifications; 
5. Tissue visibility at the skin line; 
6. Noise, i.e., noise obscuring breast structures or suggestive of structures not actually 
present; 
7. Artifacts due to image processing, detector failure and other factors external to the 
breast on soft-copy displays; and 
8. Ability to characterize a Mass (When Present) based on conspicuity, margin 
sharpness, shape; 
9. Ability to characterize Calcifications (When Present) based on conspicuity, 
sharpness/shape, distribution; 
10. Ability to characterize an Architectural Distortion (When Present) based on conspicuity, 
sharpness; 
11. Diagnostic confidence.   
 
 
 

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8.4.2 Core Reading Center 
 
The reading process with 6 radiologists selected for the feature comparison reader study will 
be conducted at International HealthCare, LLC in Norwalk, CT. 
 
8.4.3   Preparation of Cases for Interpretation 
 
To maintain subject confidentiality, no identifying patient data will be displayed. Unique 
image identifiers associated with the case ID number will be visible in each DICOM header 
for tracking purposes. To maintain reader confidentiality, a unique ID number will be 
assigned to each radiologist participating in the reader study for entry on the CRFs. 
 
8.4.4 Workflow for the Interpretation of Cases 
Readers will be shown side-by-side images of the same breast reconstructed with the 
modified and original processing methods.  One breast per subject (two views per breast) 
will be assessed by the readers. Readers will be blinded to the image reconstruction and 
processing methods.  Each reader will be given a unique sample of cases to review.  The 
order of the subjects and location (left or right review workstation high resolution monitor) of 
the images with modified processing will be randomized for each reader.   
Within each stratum, cases will be randomly selected so that 10% have extremely dense 
breasts, 40% have heterogeneously dense breasts, 40% have scattered fibroglandular 
breasts, and 10% have fatty breasts.   
 
Readers may interpret the preloaded cases in their assigned randomized order with the use 
of barcode scanner/barcodes.  
General instructions for the readers are as follows: 
The reader is to compare the tomosynthesis image on the left monitor to the tomosynthesis 
image on the right monitor. One CRF will be completed for each view (CC and MLO) for 
each case (breast).  
For each case that has a lesion, the reader is to document lesion type, quadrant and slice 
number.  
A study scribe representing the sponsor will capture the radiologist’s results on the CRFs to 
ensure completeness and allow the radiologist to focus on evaluation of image sets.  
 
 
 

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9. Statistical Analysis 
The proportion of cases where the readers judged the modified image processing as non-
inferior will be calculated.  Non-inferiority will be defined as a score of equivalence between 
modified and original or a score indicating the modified image processing is superior.  For 
each reader, the proportion of cases judged as non-inferior with modified processing will be 
calculated for each feature and each view in Table 3.  A pooled estimate will also be 
calculated where the results over all readers and views will be combined.  95% percentile 
bootstrap CIs will be constructed for the pooled proportions of cases judged as non-inferior 
with the modified processing.  These CIs will be reported for each feature. 
The null hypothesis is that the pooled proportion of cases judged as non-inferior with 
modified image processing is <0.50, versus the alternative hypothesis that the pooled 
proportion is >0.50. If the 95% CI does not contain values <0.50, then the null hypothesis 
will be rejected. These hypotheses will be evaluated for each of the seven general 
mammographic features.  If the null hypothesis is rejected for each of the seven general 
features, then it will be concluded that the readers’ subjective evaluation of the features on 
the modified imaging is non-inferior to the original imaging. 
 
9.1. Analysis Set 
We plan to include all readers’ interpretations of all cases in the analysis set. If any protocol 
deviations or violations occur, Fujifilm will report these to the statistician. The statistician will 
evaluate these to determine their impact on the validity of the study data and will determine 
whether any affected data points should be excluded from analysis. 
 
9.2 Analysis of Primary Objective 
The primary objective of this study is non-inferiority in each of the seven general mammographic 
features of the modified processing.  
The proportion of cases where the readers judged the modified image processing as non-
inferior will be calculated.  Non-inferiority will be defined as a score of equivalence between 
modified and original or a score indicating the modified image processing is superior.  For each 
reader, the proportion of cases judged as non-inferior with modified processing will be 
calculated for each general mammographic feature.  A pooled estimate will also be calculated 
where the results over all readers will be combined.  95% percentile bootstrap CIs will be 
constructed for the pooled proportions of cases judged as non-inferior with the modified 
processing.  These CIs will be reported for each of the 7 general mammographic features. 
 
 
9.3 Sample Size Justification 
 
The following assumptions were made for determining sample size for the primary objectives: 
 
 
One breast per subject (two views) 
 
Each of six readers scores an independent sample of cases; thus, there is no 
correlation between readers’ interpretations. 
 
50% of cases have dense breasts 
 
>80% power is required 

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 
2.5% type I error rate (Note that hypothesis rejection depends on the lower bound of 
the 95% CI being greater than 0.50.) 
 
Based on these assumptions, sample size was determined as follows: 
𝑀= {1.96 × √0.5(1 −0.5) + 0.84√𝑝(1 −𝑝)}2
[𝑝−0.5]2
 
where p is the proportion of comparisons judged as non-inferior under the alternative 
hypothesis.  The sample size is given by N=M/(# readers).  Table 4 summarizes the number of 
subjects needed per reader as a function of the proportion of cases judged as non-inferior with 
the modified processing.  
 
Table 4. Number of Subjects Needed Per Reader for Tests of Non-inferiority 
 
# readers 
Proportion of Comparisons Judged as Non-inferior with 
Modified Processing (DVIIm plus ISR) 
 
0.55 
0.56 
0.57 
0.60 
6 
131 
91 
67 
33 
 
 
A study with 600 total subjects (i.e. 100 cases evaluated per reader) is proposed.  This 
sample size would provide slightly more than 80% power to reject the primary null hypothesis, 
as long as >56% of cases are judged non-inferior. 
 
 
 
 
10. Sponsor and Investigational Site Requirements (Study Administration) 
10.1 
 Ethics 
10.1.1 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  
 
10.1.2 Institutional Review Board 
 
The sponsor and investigator(s) shall assure that an IRB, constituted in accordance with 
21CFR812 Subpart D and ICH guidelines for GCP (ICH E6 GCP) will provide initial and 
continuing review of the study. 
 
Prior to enrollment of study subjects in the image acquisition portion of the study, 
documented IRB approval of the protocol, the informed consent form, and any other 
written materials supplied to the subjects, including any advertisements for subject 
recruitment, was obtained and provided to the sponsor or its designated 
representative(s). 

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Prior to commencement of the reader study portion of the study, documented IRB 
approval of the protocol, the reader informed consent form, and any other written 
materials supplied to the readers must be obtained by the sponsor or its designated 
representative(s). 
 
The IRB must also be informed of any protocol amendments prior to implementation. 
The sponsor must provide reports of any change in research activity (e.g., the 
completion, termination, or discontinuation of the study) to the IRB. Annual review 
documentation will be submitted to the IRB 90 days prior to the IRB approval expiration. 
 
 
 

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10.2 
Reader Informed Consent 
Each reader must provide written informed consent before participating in the reader 
study of this protocol. 
 
10.3 
Protocol Compliance 
Except for a change that is intended to eliminate an apparent immediate hazard to a 
study subject, the protocol shall be conducted as described. Any such change must be 
reported immediately to Fujifilm or its representative(s) and the governing IRB. 
10.3.1 Protocol Amendments 
Protocol amendments will be prepared and approved by Fujifilm or its authorized 
designee. All protocol amendments will be signed by the investigator and submitted to 
the IRB for review prior to implementation. Documentation of IRB approval must be 
provided to Fujifilm or its representative. If an amendment significantly alters the study 
design, increases potential risk to the subject, or otherwise affects statements in the 
informed consent, the informed consent must be revised and submitted to the IRB for 
review and approval. The approved informed consent form must be used to obtain 
consent from new subjects enrolled in the study and must also be used to re-consent 
subjects already enrolled in the study, if they are affected by the amendment. 
 
10.4 
Retention of Study Records 
All documents pertaining to the conduct of this clinical study – including CRFs, informed 
consent forms, source documents, and other records must be retained during the 
investigation, unless otherwise requested by the sponsor, for a period of 2 years after the 
later of the following 2 dates [21CFR812.140 (d)]: 
 
 
Records are no longer required for the purposes of supporting a regulatory 
submission to the FDA. 
 
OR 
 
 
Following the termination or withdrawal of the regulatory submission. 
 
The principal investigator must contact Fujifilm in writing prior to the destruction of any study 
records or in the event of accidental destruction or loss of the documents. If the principal 
investigator leaves the institution where the study is being conducted, the principal 
investigator must contact the sponsor to arrange for transfer of responsibilities and 
alternative record storage options, if applicable. 
Study documentation includes all CRFs, data correction forms, source documents, 
monitoring logs, sponsor-investigator correspondence, protocols and amendments, ethics 
committee correspondence and approvals, signed consent forms, etc. Source documents 
include all original records or observations, results and activities necessary to reconstruct 
and evaluate the study.  
 
 
 

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10.5 
Data Collection and Management 
10.5.1 General 
All data entry will be completed using paper Case Report Forms, following the guidelines 
established in the Data Management Plan.  
The privacy of participating subjects must be maintained in accordance with the HIPAA 
privacy ruling and disclosed per 24CFR50. 
The CRFs will be data entered, and then reviewed for accuracy and completeness by a 
study monitor representing Fujifilm, as well as reviewed by DMC staff prior to data 
transfer to the statistician.  
10.5.2 Data Management Center 
The responsibilities of the DMC will include monitoring and oversight of the collection 
efforts, performance of the data audits, facilitating data entry into a computerized 
database, and providing the data to the statistician. 
The DMC responsibilities will include oversight of the data collection efforts (excluding 
image data, which will be collected by Fujifilm or its designees), facilitation of data entry 
into the computerized database, all final data cleaning, and performance of a final data 
quality-control audit prior to database lock. 
CRFs will be logged and tracked when received by the DMC. CRFs will then be entered 
and stored in a 21 CFR Part 11 compliant clinical database. Upon completion of the 
study and resolution of all outstanding DCFs, the database will be locked and datasets 
necessary for analysis and reporting will be generated and provided to the statistician for 
final analysis. 
 
10.6 
Confidentiality 
10.6.1 Subject Confidentiality 
To maintain subject confidentiality, no identifying patient data will be displayed. Unique 
image identifiers associated with the case ID number will be visible on each image for 
tracking purposes. A unique ID, one per case per modality will be assigned to each case 
whose images are selected for the reader study and will be the only subject identifier on 
all study-related documentation.   
Prior to the initiation of the study, Fujifilm or its authorized representative will provide the 
readers with adequate training related to the identification. The subject’s unique identifier 
may be displayed on the softcopy image as an overlay. The overlay may be turned on 
and off as necessary during the reader studies for reference. 
10.6.2 Reader Confidentiality 
Information collected during the reader study will be reported in such a way as to 
preclude identification of any individual radiologist’s performance. To maintain reader 
confidentiality, a unique ID number will be assigned to each radiologist participating in 
the reader study for entry on the CRF’s. A master list of these ID numbers for the 
radiologists participating in the reader study will be securely maintained by the Fujifilm 
project manager. 

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10.6.3 Transfer of Confidential Information to the Sponsor or the DMC 
This reader study utilizes data from the Fujifilm library that was obtained in Fujifilm 
protocol FMSU2013-004A. All data utilized for this study (photocopies of radiology, 
pathology and clinical reports as well as images) was de-identified prior to removal from 
the acquisition center(s).  
 
10.7 
Study Monitoring 
 
Fujifilm and/or its designees will monitor the study, verify the collection of data, and confirm 
that the study is being conducted according to the protocol. The CRF data will be recorded. 
The study may be audited by representatives from the FDA or other regulatory agencies, 
who also shall be allowed access to study documents. 
If Fujifilm, the principal investigator, the IRB, or a regulatory authority discover conditions 
arising during the study that indicate that the study should be halted or that the study 
center’s participation in the study should be terminated, this action may be taken after 
appropriate consultation between Fujifilm, its designee, and the investigator(s). 
10.8 
Sponsor Audits 
 
Individuals appointed by the sponsor may visit the CRO to conduct an audit of the study 
GCPs. The purpose of the visit will be to determine adherence to the protocol, applicable 
regulations and the sponsor’s procedures in addition to the assessing the accuracy of the 
study data (Inspection Readiness). Prior to initiating this audit, the CRO will be contacted by 
the sponsor to arrange a convenient time for this visit. 
 
10.9 
Inspection by a Regulatory Agency 
 
At some point during the study, the investigator may be visited by a regulatory agency (e.g., 
FDA) to conduct an inspection of the study. The purpose of this visit will be to determine 
adherence to the protocol and regulatory requirements for conducting clinical studies. The 
investigator must immediately notify Fujifilm when contacted by a regulatory agency for the 
purposes of conducting an inspection of the Fujifilm’s study. 
 
10.10 
Financial Disclosure 
 
In accordance with 21CFR54, the principal investigator and the study readers will provide 
Fujifilm or its designee sufficient and accurate information on financial interests (proprietary or 
equity interests and payments exclusive of clinical study costs) to allow complete disclosure 
documenting lack of conflict of interest. The principal investigator and study readers shall 
promptly update this information with any relevant changes that occur during the course of the 
study, at the completion of the study, and for a period of 1 year following the completion of the 
study. 
 
 
 

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10.11 
Study or Study-site Termination 
 
If Fujifilm, the principal investigator, the IRB, or a regulatory authority discover conditions 
arising during the conduct of the study that indicate that the study should be halted or that 
the study center should be closed, this action may be taken after appropriate consultation 
between Fujifilm and the principal investigator. Conditions that may warrant termination of 
the study include, but are not limited to, the following: 
 
A decision on the part of Fujifilm to suspend or discontinue testing, evaluation, or 
development of a product. 
The study center may warrant closure/termination for the following reasons: 
 
Failure of the investigator to comply with pertinent regulatory authority regulations. 
 
Knowing submission of false information from the research center to Fujifilm, study 
monitor, or a regulatory authority. 
 
Insufficient adherence to the protocol requirements. 
Study termination and follow-up will be performed in compliance with the conditions set forth 
in 21CFR812.150 (a) (2). 
 
 
 

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11 
Appendices 
Appendix A: Fujifilm FFDM and DBT Image Acquisition and Display 
Note: The proposed brand and/or configuration of the ASPIRE products are subject to change. 
Overview of ASPIRE Cristalle DBT Option and ASPIRE Bellus II 
Fujifilm’s ASPIRE Cristalle DBT Option (Figure A) mammography acquisition system generates 
both FFDM and DBT images. It is comprised of the X-ray exposure unit and acquisition 
workstation, and is FDA PMA approved (P160031) for 2D mammography and DBT image 
acquisition.  
Fujifilm’s ASPIRE Bellus II (Figure B) mammography review workstation displays and supports 
the physician’s review of 2D mammography and DBT images. It is composed of the display 
accessories of the ASPIRE Cristalle and includes the major components of a PC (with image 
review and manipulation software installed), a console monitor, and two high-resolution grayscale 
diagnostic display monitors, and is FDA cleared (K171463) 
 
 
 
Figure A. ASPIRE Cristalle DBT Option - 
Fujifilm’s mammography acquisition system. 
Figure B. ASPIRE Bellus II - 
Fujifilm’s mammography viewer. 
Acquisition of FFDM and DBT Images by ASPIRE Cristalle DBT Option (Figure A) 
All FFDM and DBT images of the enrolled study subjects were acquired on the ASPIRE 
Cristalle system with DBT option. For each study subject, the DBT and FFDM images were 
acquired under the same breast compression for each of the LCC, RCC, LMLO and RMLO 
views.   
Display of FFDM and DBT Images on ASPIRE Bellus II (Figure B) 
Mammography images are displayed on the ASPIRE Bellus II for the physician’s review. 
The console allows the user to manage various aspects of the system configurations and 
setup, including the modality work list, local archive, communications, and the selection of 
images to be displayed on the two high-resolution grayscale diagnostic display monitors. 
The viewer supports typical image-manipulation functions, such as windowing, leveling, 
zooming, etc. 
 
 
Acquisition 
Workstation 
Exposure Unit 
Viewer 
Console 
PC 

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Appendix B: Inclusion and Exclusion Criteria from FMSU2013-004A 
Study Population 
All female subjects, of any ethnic or racial origin, who are appearing for a routine screening 
examination or have been referred for further diagnostic evaluation after a screening 
examination (within 60 days) or have a 4-view mammogram (within 60 days) due to clinical 
concerns and receive a BI-RADS assessment of category 4 or 5 after diagnostic workup and 
are scheduled for biopsy will be eligible to participate in the study.  
Subjects will receive a written explanation of the study and will be asked to provide written 
informed consent to participate. Once eligibility is confirmed and informed consent has been 
obtained, the subjects will be enrolled in the study. 
 
Inclusion Criteria 
Subjects enrolled must meet all the following inclusion criteria: 
 
Screening Subjects 
o Be at least 40 years of age, are 
o Asymptomatic,  
o Scheduled for a routine screening mammogram,  
 
Recall Subjects 
o Be at least 18 years of age 
o Received a BIRADS 0 within the last 60 days 
o Are recalled for additional imaging 
 
Diagnostic Subjects 
o Be at least 18 years of age,  
o Scheduled for a biopsy due to an assessment of BI-RADS® 4 or 5 after diagnostic 
work-up of a suspicious screening or clinical finding within the last 60 days.   
 
Have the ability to understand the requirements of the study, to provide written informed 
consent, and to comply with the study protocol, and 
 
Meet none of the exclusion criteria. 
Exclusion Criteria 
Subjects will be excluded from participating in the study if they meet any one or more of the 
following exclusion criteria: 
 
Presence of a breast implant. 
 
Women with only a single breast; for example, post mastectomy patients. 
 
Is pregnant or believes she may be pregnant. 
 
A woman who has delivered and who has expressed the intention to breast-feed or is 
currently breast-feeding. 
 
A woman who has significant existing breast trauma within the last one year. 
 
Has self-reported severe non-focal or bilateral breast pain affecting subject’s ability to 
tolerate digital mammography and/or breast tomosynthesis examinations. 
 
A woman who has had a mammogram performed for the purpose of therapy portal 
planning within the last year. 
 
Cannot, for any known reason, undergo follow-up digital mammography and/or breast 
tomosynthesis examinations (where clinically indicated) at the participating institution. 
 
Is an inmate (see US Code of Federal Regulations 45CFR46.306)