A Multi-Reader Multi-Case Controlled Clinical Trial to Evaluate the Comparative Accuracy of the Fujifilm DBT Plus S-View Versus FFDM Alone in the Detection of Breast Cancer - A Pilot Study
Conditions: Breast Cancer
Sponsor: Fujifilm Medical Systems USA, Inc.

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A Multi-Reader Multi-Case Controlled Clinical Trial to Evaluate the 
Comparative Accuracy of the Fujifilm DBT plus S-View versus 
FFDM Alone in the Detection of Breast Cancer 
 
- A Pilot Study 
 
 
 
 
 
 
 
 
 
FUJIFILM Medical Systems U.S.A., Inc. 
419 West Avenue 
Stamford, CT 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 Acceptance of this document constitutes agreement by the recipient that no unpublished 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 
Definitions ................................................................................................................................. 6 
Tables and Figures ................................................................................................................. 10 
1. 
Sponsor Protocol Approval Signature Page .................................................................. 11 
2. 
Investigator Agreement Signature Page......................................................................... 12 
3. 
Protocol Synopsis ............................................................................................................ 13 
4. 
Fujifilm FMSU2013/2017 Series Protocols ...................................................................... 17 
5. 
Investigators and Study Administrative Structure ........................................................ 18 
6. 
Background and Rationale .............................................................................................. 19 
7. 
Investigational Plan ......................................................................................................... 21 
7.1. 
Purpose ..................................................................................................................... 21 
7.2. 
Study Endpoints ....................................................................................................... 21 
7.3. 
Pilot Study Population .............................................................................................. 21 
7.3.1. 
Case Reference Standard.................................................................................... 22 
7.3.2. 
Sample Size and Case Mix .................................................................................. 22 
7.3.3. 
Inclusion and Exclusion Criteria ........................................................................... 22 
7.3.4. 
Case selection and Targeted Distribution ............................................................. 23 
      7.4.   Risk/Benefit Assessment …...……….………………………………..………………….24 
8. 
The Truthing Process ...................................................................................................... 25 
8.1. 
Purpose ..................................................................................................................... 25 
8.2. 
Qualification Criteria and Training for the Truther ................................................. 25 
8.3. 
Conduct of the Truthing Process ............................................................................ 25 
8.3.1. 
Core Reading Center ........................................................................................... 25 
       8.3.2.      Preparation of Cases for Truthing….………..………………………………………..26 
8.3.3. 
Workflow for the Truthing Process ....................................................................... 26 
9. 
Reader Selection and Training ........................................................................................ 27 
9.1. 
Purpose ..................................................................................................................... 27 
9.2. 
Selection and Qualification Criteria for Readers .................................................... 27 
9.3. 
Conduct of the Training Process ............................................................................. 27 
9.4. 
Conduct of the Reading Process ............................................................................. 27 
9.4.1. 
Purpose and Conduct .......................................................................................... 28 
       9.4.2       Core Reading Center…….………………………….…………….……………………28 
9.4.3. 
Preparation of Cases for Interpretation ................................................................ 28 
9.4.4. 
Workflow for the Interpretation of Cases .............................................................. 28 
9.4.5. 
Reading Sessions with a Memory Washout Period .............................................. 30 
10. The Lesion Matching Process ......................................................................................... 32 
10.1. 
Purpose .................................................................................................................. 32 
10.2. 
Qualification Criteria and Training for the Lesion Matcher ................................ 32 

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10.3. 
Conduct of the Lesion Matching Process ........................................................... 32 
10.3.1. 
Core Matching Center ...................................................................................... 32 
10.3.2. 
Preparation of Cases for Lesion Matching ........................................................ 32 
10.3.3. 
Workflow for the Lesion Matching Process ....................................................... 32 
11. Statistical Analysis .......................................................................................................... 34 
11.1 
Analysis Set .............................................................................................................. 34 
11.2 
Multiple Centers (pooling) ........................................................................................ 34 
11.3 
Derived Variables for Statistical Analyses .............................................................. 34 
11.3.1 
Per-subject scoring: POM and BI-RADS .............................................................. 35 
11.3.2 
Per-subject scoring: Recall .................................................................................. 36 
11.3.3 
True Positive, False Negative, True Negative, and False Positive ....................... 37 
11.4 
Analysis of Primary Endpoint .................................................................................. 38 
11.5 
Analysis of Secondary Endpoints ........................................................................... 38 
12. Sponsor and Investigational Site Requirements (Study Administration) .................... 39 
12.1 
Ethics ......................................................................................................................... 39 
12.1.1 
Ethical Conduct of the Study ................................................................................ 39 
12.1.2 
Institutional Review Board.................................................................................... 39 
12.2 
Reader Informed Consent ........................................................................................ 40 
12.3 
Protocol Compliance ................................................................................................ 40 
12.3.1 
Protocol Amendments .......................................................................................... 40 
12.4 
Retention of Study Records ..................................................................................... 40 
12.5 
Data Collection and Management ............................................................................ 41 
12.5.1 
General ................................................................................................................ 41 
12.5.2 
Data Management Center .................................................................................... 41 
12.5.3 
New Suspicious Findings ..................................................................................... 41 
12.6 
Confidentiality ........................................................................................................... 42 
12.6.1 
Subject Confidentiality ......................................................................................... 42 
12.6.2 
Reader Confidentiality .......................................................................................... 42 
12.6.3 
Transfer of Confidential Information to the Sponsor or the DMC .......................... 42 
12.7 
Study Monitoring ...................................................................................................... 42 
12.8 
Sponsor Audits ......................................................................................................... 42 
12.9 
Inspection by a Regulatory Agency ......................................................................... 42 
12.10 
Financial Disclosure.............................................................................................. 43 
12.11 
Study or Study-site Termination .......................................................................... 43 
13. References........................................................................................................................ 44 
14. Appendices....................................................................................................................... 45 
Appendix A: Fujifilm FFDM and DBT Image Acquisition, Display, and Interpretation .... 45 
Appendix B: Inclusion and Exclusion Criteria from FMSU2013-004A, Version 3.0 ......... 47 
Inclusion Criteria ................................................................................................................ 47 
Exclusion Criteria ............................................................................................................... 47 

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Abbreviations 
Abbreviation 
Explanation 
ACR® 
American College of Radiology 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Receiver Operating Characteristic (ROC) Curve 
BI-RADS® 
Breast Imaging Reporting and Data System 
CC 
Cranio-Caudal 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
DBT 
Digital Breast Tomosynthesis 
DCF 
Data Clarification Form 
DMC 
Data Management Center 
eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
FP 
False Positive 
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 
IDC 
Invasive Ductal Carcinoma 
IDE 
Investigational Device Exemption 
ILC 
Invasive Lobular Carcinoma 

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IRB 
Institutional Review Board 
LCC 
Left Cranio-Caudal 
LMLO 
Left Medio-Lateral Oblique 
MDR 
Medical Device Reporting 
MLO 
Medio-Lateral Oblique 
MQSA 
Mammography Quality Standards Act 
MRMC 
Multi-Reader Multi-Case 
PHI 
Protected Health Information 
PMA 
Premarketing Approval Application 
POM 
Probability of Malignancy 
RCC 
Right Cranio-Caudal 
RMLO 
Right Medio-Lateral Oblique 
ROC 
Receiver Operating Characteristic 
S-View 
Synthesized View 
STARD 
Standards for Reporting of Diagnostic Accuracy 
TP 
True Positive  
 
 

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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 
BI-RADS® Score 
Derived variable based on lesion matching and requiring correct lesion localization 
ASPIRE Bellus II 
Fujifilm mammography viewer (see Appendix A) where the FFDM and DBT plus S-View 
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. 
ASPIRE Cristalle 
DBT Option with S-
View 
ASPIRE Cristalle DBT Option (P160031) with synthesized view (S-View), where the S-
View images are created from the reconstructed DBT images. 
“CAUTION: Investigational Device Limited by U.S. Federal Law to Investigational Use. 
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. 
Cancer Recall Rate 
The rate (or fraction) of cancer case(s) correctly recalled by the reader 
Correct Lesion 
Localization 
The location and type of a finding annotated by the reader matches those of a lesion 
annotated by the truther, as determined by the Lesion Matcher. 
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.  

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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.  
DBT plus S-View 
Examination 
Each DBT plus S-View 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 plus S-View images are displayed and interpreted by the physician on 
the ASPIRE Bellus II.  
DBT plus S-View 
Images 
DBT plus S-View images for each of the RCC, LCC, RMLO, LMLO for each breast 
DBT plus S-View 
Read 
The physician reads (interprets) the DBT plus S-View images displayed on the ASPIRE 
Bellus II (see Appendix A) 
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. 
False Positive 
A false positive is when a negative case has been incorrectly identified as a positive 
case. 
FFDM Examination 
Each FFDM Examination has two parts: 
 
Acquisition: Acquisition of FFDM images for each of the standard bilateral CC and 
MLO views (RCC, LCC, RMLO, LMLO): 
 
Review: FFDM images are displayed and interpreted by the physician on the 
ASPIRE Bellus II. 
FFDM Images 
FFDM mammograms; comprised for the four standard views (RCC, LCC, RMLO and 
LMLO) images captured by the ASPIRE Cristalle (see Appendix A).  
FFDM Read 
The physician interprets the FFDM images displayed on the ASPIRE Bellus II (see 
Appendix A) 
FFDM Views 
Standard CC and MLO views for each breast. 
FMSU2013-004A 
Acquisition of Digital Mammography and Breast Tomosynthesis Images for Clinical 
Evaluation of Fujifilm Digital Breast Tomosynthesis 
FMSU2013-004E 
A Multi-Reader Multi-Case Controlled Clinical Trial to Evaluate the Comparative Accuracy 
of the Fujifilm FFDM Plus DBT versus FFDM Alone in the Detection of Breast Cancer – A 
Pilot Study 
FMSU2013-004F 
A Multi-Reader Multi-Case Controlled Clinical Trial to Assess the Adequacy of the Fujifilm 
FFDM and DBT Reader Training Program – A Pilot Study 
FMSU2017-002A 
A Multi-Reader Multi-Case Controlled Clinical Trial to Evaluate the Comparative Accuracy 
of Fujifilm DBT plus S-View versus FFDM Alone in the Detection of Breast Cancer – A 
Pilot Study 
FMSU2017-002B 
A Multi-Reader Multi-Case Controlled Clinical Trial to Evaluate the Comparative Accuracy 
of Fujifilm DBT plus S-View versus FFDM Alone in the Detection of Breast Cancer – A 
Pivotal Study 
Forced BI-RADS 
A BI‐RADs assessment category of 1 through 5, which the readers must give if they had 

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given the case an initial BI‐RADs score of 0. This score is based solely on the 
mammogram images presented to the reader and not the actual results of any additional 
work‐up that may have been performed pertaining to that specific case 
Fujifilm 
FUJIFILM Medical Systems, U.S.A., Inc.  
IA Site DBT Reader 
An image-acquisition site reader is a qualified radiologist who interprets the DBT images 
at the time of image acquisition (see FMSU2013-004A) and, in doing so, contributes to 
the reference standard for those images. 
IA Site FFDM Reader 
An image-acquisition site reader is a qualified radiologist who interprets the FFDM 
images at the time of image acquisition (see FMSU2013-004A) and, in doing so, 
contributes to the reference standard for those images. 
Initial BI-RADS 
In the reader study, a BI-RADS assessment category of either a 0 (incomplete), 1 
(negative) or 2 (benign); used as a preliminary assessment of a case.  
Lesion Location 
The location of the lesion marked by the reader study reader  
Lesion Matcher 
 
 
 
An expert not associated with diagnosing cases at the image-acquisition sites or serving 
as a reader interpreting images on this reader study. This expert may be an expert 
mammography technologist with an active license or a board-certified radiologist and 
MQSA-qualified mammographer; if a board-certified radiologist and MQSA-qualified 
mammographer, this expert may be the same person as the truther. 
Mammographically 
Detectable Finding 
A mammographically detectable finding is a breast finding detectable by either FFDM or 
DBT plus S-View as determined by the truther. 
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. 
Non-Cancer Recall 
Rate 
The rate (or fraction) of non-cancer cases incorrectly recalled by the reader 
Per-Subject Analysis 
Requiring Correct 
Localization 
Per-subject analysis is the analysis of BI-RADS®, POM, or recall ratings assigned to the 
study subject requiring correct lesion localization. 
POM Score 
The study reader’s assigned probability that a finding is malignant (POM score ranges 
from 0 to 100%). 
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. 
Recall Score 
The recall score indicates whether a finding will be recalled or not (e.g., recall score “1” is 
recall and “0” is no-recall). 
Reference Standard 
The reference standard (also often called the “gold standard” or “ground truth” in the 
imaging community) for patient data indicates whether the disease/condition/abnormality 
is present and may include such attributes as the extent or location of the 
disease/condition/abnormality. 
Reference Standard 
Biopsy or surgery: At least one lesion is confirmed as malignant by biopsy or surgery. 

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for Cancer Cases 
Reference Standard 
for Non-cancer 
Cases 
Established by biopsy or surgery for benign cases, or interpretation by radiologists at the 
enrolling site for recall and normal cases. 
Note: Under the FMSU2013-004A image acquisition protocol, subjects with no lesions 
biopsied were to have a 1-year follow-up mammogram (collected within 320 to 455 days 
following the original mammogram) with no malignancy discovered. 
ROC Curve 
A Receiver Operating Characteristic (ROC) curve is a plot of Sensitivity versus 1-
Specificity and is a summary of diagnostic performance of a device or a clinician.  
Screening 
Population 
Asymptomatic subjects who present for screening mammograms (FFDM and/or DBT). 
Sensitivity 
Sensitivity is defined as the probability that a test is positive for a population of patients 
with the disease/condition/abnormality. 
Specificity 
Specificity is defined as the probability that the test is negative for a population of patients 
without the disease/condition/abnormality (i.e., normal subjects). 
Standard views 
Standard CC and MLO views for each breast (RCC, LCC, RMLO, LMLO). 
Subject reference 
standard 
The standard against which blinded readers’ interpretations will be compared to 
determine the accuracy of their interpretations  
Symptomatic 
Subjects 
Subjects recommended for diagnostic digital mammography and/or breast tomosynthesis 
based on screening mammogram and/or breast tomosynthesis results or clinically 
detectable signs and symptoms. 
Synthesized View (S-
View) Images 
The synthesized view image for each of the LCC, RCC, LMLO, or RMLO views is created 
from “combining” the DBT images of that view to a single synthetic view image. 
True Positive 
A true positive is when a positive case has been correctly identified as a positive case. 
Truther 
An expert radiologist not associated with diagnosing cases at the image-acquisition sites 
or interpreting images in the reader study who will determine reference standard status 
and annotate lesions 
Truthing Process 
The truthing process describes the process that the truther follows to confirm the 
reference standard for each case, based on materials from the image acquisition site 
including the study subject’s FFDM and DBT plus S-View images. For each case with at 
least one (1) cancerous lesion, the truther will review the images and identify, confirm, 
and annotate lesions (including the types of lesions visible within the FFDM and/or DBT 
plus S-View images, the locations of the lesions, and the characteristics of the lesions) on 
the eCRF. 
 
 
 
 
 
 
 
 
 
 

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Tables and Figures 
 
Table 1: Image acquisition sites and Principal Investigators ......................................................22 
Table 2: Targeted distribution of mammographic finding types (approximation) ........................23 
Table 3: Targeted distribution of mammography breast composition (approximation) ...............24 
Table 4: Probability of malignancy (POM) guidance ..................................................................29 
Table 5: Per-subject POM and BI-RADS assessment categories ..............................................36 
Table 6: Per-subject recall scores (requiring correct lesion localization) ....................................37 
 
Figure A. ASPIRE Cristalle .......................................................................................................45 
Figure B. ASPIRE Bellus II.….…….……….……….….………………………….…………………..45 
  

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1. Sponsor Protocol Approval Signature Page 
Study Title 
A Multi-Reader Multi-Case Controlled Clinical Trial to Evaluate 
the Comparative Accuracy of Fujifilm DBT plus S-View versus 
FFDM Alone in the Detection of Breast Cancer 
– A Pilot Study 
Protocol Number 
FMSU2017-002A 
Effective Date  
October 10, 2017 
Study Sponsor 
FUJIFILM Medical Systems U.S.A., Inc. 
419 West Avenue 
Stamford, Connecticut 06902, U.S.A. 
 
 
 
 
 
 
 
 
 
 
 
 
 
FUJIFILM Medical Systems U.S.A., Inc. 
Approval 
Name, Title 
 
Signature 
 
Date 
 
 
 
 

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2. Investigator Agreement Signature Page 
Study Title 
A Multi-Reader Multi-Case Controlled Clinical Trial to Evaluate the 
Comparative Accuracy of Fujifilm DBT plus S-View versus FFDM 
Alone in the Detection of Breast Cancer 
– A Pilot Study 
Protocol Number 
FMSU2017-002A 
Effective Date  
October 10, 2017 
Study Sponsor 
FUJIFILM Medical Systems U.S.A., Inc. 
419 West Avenue 
Stamford, Connecticut 06902, U.S.A. 
Primary Investigator 
Laurie L. Fajardo, M.D., MBA, FACR, FSBI 
Radiology Consultant 
1730 Lucky John Dr. 
Park City, UT 84060 
 
 
 
 
 
I, the primary investigator named above, acknowledge the receipt of this protocol. I 
have read this protocol in its entirety and agree to conduct this study according to this 
protocol and all applicable regulations/guidelines. 
 
Primary Investigator 
 
Signature 
 
Date 
 
 
 
 

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3. 
Protocol Synopsis 
SPONSOR NAME 
FUJIFILM Medical Systems U.S.A., Inc. 
PROTOCOL NUMBER 
FMSU2017-002A 
STUDY TITLE 
A Multi-Reader Multi-Case Controlled Clinical Trial to Evaluate the Comparative 
Accuracy of Fujifilm DBT plus S-View versus FFDM Alone in the Detection of Breast 
Cancer 
– A Pilot Study 
DEVICE NAME 
Fujifilm ASPIRE Cristalle with DBT Option 
PURPOSE 
The purpose of the pilot reader study is to provide credible performance estimate 
information in order to properly plan, design, and power the pivotal study. 
(1) the radiologists’ performance metrics for the two reading modalities, i.e., FFDM 
read on the ASPIRE Bellus II workstation (“FFDM”), and Synthesized (S-View) 
read in conjunction with DBT read on the ASPIRE Bellus II workstation (“DBT 
plus S-View”);  
(2) the magnitude and direction of differences between performance metrics for the 
two modalities; and  
(3) variance components and correlations that would influence sample sizes and 
case mix for the pivotal reader study (FMSU2017-002B) comparing performance 
metrics between the two modalities.  
The AUC, sensitivity, specificity, and recall rate are the key performance indices for 
the study analysis. We are particularly interested in performance in the subgroups of 
biopsy benign and recall cases, as this will influence case mix for the pivotal reader 
study. 
STUDY ENDPOINTS 
 
All of the following endpoints are measured on the FFDM read, DBT plus S-View read, 
and their difference. All measurements require correct lesion localization. 
The primary endpoint is: 
 
Non-inferior per-subject average area under the ROC curve (AUC) for 
DBT plus S-View versus FFDM, based on per-subject POM scores and 
requiring correct lesion localization 
The secondary endpoints are: 
a. Superior per-subject average AUC for DBT plus S-View versus FFDM 
b. Non-inferior and/or superior per-subject average recall rate for all non-cancer 
cases for DBT plus S-View versus FFDM 
c. Superior per-subject average specificity for DBT plus S-View versus FFDM 
d. Non-inferior and/or superior per-subject average sensitivity for DBT plus S-View 
versus FFDM 
e. Non-inferior per-subject average recall rate for DBT plus S-View versus FFDM 
for all cancer cases 
 
CORE READING CENTER 
The pilot study will be performed at International HealthCare, LLC in Norwalk, CT.  

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PRIMARY INVESTIGATOR, 
TRUTHER, READERS, AND 
LESION MATCHER 
The primary investigator for this study is Laurie Fajardo, MD, MBA, FACR, FSBI. 
The truther, the lesion matcher, and the pilot study radiologist readers shall meet all 
criteria for their respective roles as specified in the investigational plan.  
The truther, the lesion matcher, and the pilot study readers will, respectively, 
participate in a training session to ensure their understanding of the ASPIRE Bellus II 
workstation, the protocol, the study eCRFs, study processes, GCP, and their 
obligations as study participants. 
 
PILOT READER STUDY 
POPULATION 
- SAMPLE SIZE AND CASE 
MIX 
- CASE SELECTION AND 
TARGETED DISTRIBUTION 
 
This clinical research is a retrospective, pilot, multi-reader, multi-case (MRMC) study 
with an enriched sample of100 breast screening or diagnostic cases which will be 
selected from the library of mammograms collected under Fujifilm protocol 
FMSU2013-004A.  
All subjects in the FMSU2013-004A library previously provided written informed 
consent.  As part of the consent process, subjects agreed that image data and 
supporting documentation could be used for future research and investigations. 
Evaluable cases are defined as subjects who met all protocol inclusion/exclusion 
criteria (see Appendix B), whose true clinical status is known, and who have a 
complete set of adequate-quality mammography examinations. Image quality is 
considered adequate (as determined by the image-acquisition sites under the 
protocol) when there is sufficient anatomical coverage and contrast, and when there is 
no significant effect from motion, artifacts, or noise.  
Measures to ensure subject and reader confidentiality will include assignment of study 
unique ID numbers. 
1.  Sample Size and Case Mix 
Enriched samples size of approximately 100 cases (approximately 18 cancer 
cases and approximately 82 non-cancer cases) with the following case mix: 
 
Approximately 18 cancer cases, 17 biopsy benign cases, 19 recall cases, 
and 46 normal cases. 
2.  Case Selection and Targeted Distribution 
Cases selected for this study were those that the statistician selected for 
FMSU2013-004E and FMSU2013-004F, with the replacement of those cases 
lost to follow-up or otherwise not available for this pilot reader study. Cases 
were randomly selected to provide representative distributions of breast 
composition, finding types, and equal distribution across enrolling sites, to the 
extent that this can be accomplished using cases in the FMSU2013-004A 
case library. 
 
STUDY DESIGN 
- CASE REFERENCE 
STANDARDS 
- THE TRUTHING PROCESS 
- THE READING PROCESS 
- THE LESION MATCHING 
PROCESS 
This clinical research is a retrospective, pilot, multi-reader, multi-case (MRMC) study 
with an enriched sample of approximately 18 cancer cases and approximately 82 non-
cancer cases. 
1. Case Reference Standards 
 
The reference standard for a cancer case is a case in which at least one 
lesion is confirmed as malignant by biopsy or surgery. 
 
The reference standard for a non-cancer case is biopsy or surgery for benign 
cases, or interpretation by radiologists at the acquisition site for recall and 
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2. The Truthing Process 
The truther will review all cancer cases selected for inclusion in the reader study.  
The truther will complete an eCRF for each case, based on materials from the 
image acquisition site including mammograms. For each subject with at least one 
(1) biopsy proven malignant lesion, the truther will review the images and identify, 
confirm, and annotate lesions including the types of lesions visible within the 
mammogram and DBT image, the locations of the lesions, and the characteristics 
of the lesions on the eCRF. 
3. The Reading Process 
Approximately 6 qualified radiologists will independently perform two reads on all 
(approximately 100) cases. Each reader will read each case both as a FFDM 
read, and a DBT plus S-View read on the ASPIRE Bellus II workstation.  Each 
reader will read half the cases on FFDM and the other half of the cases on DBT 
plus S-View during one visit. The reader will then read the complimentary FFDM 
and DBT plus S-View during the second visit. In order to minimize memory recall 
bias, the two reading visits will be separated by a memory washout period of 
approximately 4 weeks. 
Interpretation instructions: The reader will complete the eCRFs for each case for 
the two reads. For each case on each read, the reader will first record whether 
there are mammographic findings and an initial BI-RADS assessment of 0, 1, or 
2. If the answer to this question is “no” the reader will be asked to confirm for this 
case: a BI-RADS assessment category of 1 or 2, a POM score following the POM 
guidance provided in Table 4, and recall decision of “no”. If the reader answers 
“yes” to whether there are mammographic findings, the reader will be asked to 
confirm an initial BI-RADS assessment category of 0, and will then provide 
detailed information on each suspicious finding (up to three findings) and the 
decision whether or not to recall the subject, as well as overall POM score and BI-
RADS assessment category. 
4. The Lesion Matching Process 
An expert not associated with diagnosing cases at the image-acquisition sites or 
serving as a reader interpreting images on this pilot reader study will conduct 
lesion matching. This expert may be an expert mammography technologist with 
an active license or a board-certified radiologist who is MQSA qualified for both 
FFDM and tomosynthesis; if a board-certified radiologist who is MQSA qualified 
for both FFDM and tomosynthesis, this expert may be the same person as the 
truther. 
 
STUDY ANALYSIS 
All primary, secondary, and additional (optional) endpoints are measured on the 
FFDM read and DBT plus S-View read, and their difference. All measurements require 
correct lesion localization. 
1.1. 
Analysis of primary endpoint 
The primary endpoint on this study is per-subject AUC requiring correct lesion 
localization. We will estimate AUCs for each reader in each review condition 
(FFDM, DBT plus S-View) based on per-subject POM scores.  
1.2. 
Analysis of secondary endpoints 
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MRMC ANOVA methods. Analysis of per-lesion sensitivity will use methods for 
clustered data from MRMC studies that take into account the correlation between 
lesions in the same case. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. Fujifilm FMSU2013/2017 Series Protocols 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fujifilm Protocol FMSU2013-004A 
Acquisition of Digital Mammography and Breast 
Tomosynthesis Images for Clinical Evaluation of Fujifilm 
Digital Breast Tomosynthesis 
Fujifilm Protocol FMSU2017-002A 
A Multi-Reader Multi-Case Controlled Clinical Trial to 
Evaluate the Comparative Accuracy of Fujifilm DBT plus 
S-View versus FFDM Alone in the Detection of Breast 
Cancer  
– A Pilot Study 
Fujifilm Protocol FMSU2017-002B 
A Multi-Reader Multi-Case Controlled Clinical Trial to 
Evaluate the Comparative Accuracy of Fujifilm DBT plus 
S-View versus FFDM Alone in the Detection of Breast 
Cancer  
– A Pivotal Study 

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5. Investigators and Study Administrative Structure 
Study Personnel: 
 
Primary 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 
Jyh-Shyan (Jesse) Lin, PhD 
Senior Manager, Regulatory, Quality and Clinical Affairs 
Phone: 301.251.1092 
Email: jlin@fujifilm.com  
Nicole Calabrese, MS 
Contract Project Manager 
Phone: 518.506.9840 
Email: ncalabrese.contractor@fujifilm.com   
Statistician 
Biostatistics Consulting, LLC 
10606 Wheatley Street 
Kensington, MD 20895 
Alicia Y. Toledano, ScD 
Phone: 301.312.8577 
Email: alicia.toledano@post.harvard.edu 
 
 

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6. Background and Rationale 
 
Breast cancer is the most common cancer among women, excluding non-melanoma skin 
cancers. The chance of a woman developing invasive breast cancer at some time in her life 
is about 1 in 8 (12%). The American Cancer Society (ACS) estimated that in 2017 about 
252,710 new cases of invasive breast cancer and about 63,410 new cases of ductal 
carcinoma in situ (DCIS) (the earliest form of breast cancer) would be diagnosed among 
women in the United States. After lung cancer, breast cancer is the leading cause of cancer 
death in women. The chance that breast cancer will be responsible for a woman's death is 
about 3%. ACS estimated that in 2015, about 40,610 women would die from breast cancer 
in the United States. Death rates from breast cancer have been declining since about 1989, 
with larger decreases in women younger than 50. These decreases are believed to be the 
result of earlier detection through screening and increased awareness, as well as improved 
treatment. 1, 2 
At present, mammography (screen-film mammography and standard full-field digital 
mammography [FFDM]) is the primary imaging modality used for early detection of clinically 
occult breast cancer. According to the 2009 report on breast cancer screening by the U.S. 
Preventive Services Task Force, screening mammography was associated with a reduction 
in the relative risk for death due to breast cancer of 14% for women aged 50 to 59 years and 
32% for women aged 60 to 69 years.3,4 In an analysis of the Swedish Mammography 
Screening in Young Women (SCRY) cohort, screening mammography was associated with 
a reduction in the relative risk for death due to breast cancer of 39% for women aged 40 to 
49 years.5 
 
FFDM is known to have three limitations.6-10 These limitations can contribute to inaccurate 
interpretations. The first limitation is lesion masking: a true lesion may not be visible on 
FFDM because it is masked by superimposed overlying or underlying normal tissue. The 
second limitation is lesion mimicry, which can occur when normal layers of tissue or isolated 
elements of calcium at different depths in the breast are superimposed along the line of 
sight and combine on the 2D-projected image to resemble a lesion. The consequence is 
false-positive reports that require the unnecessary call back of subjects for further diagnostic 
workup examinations. The third limitation addresses the inability to perceive the in-depth 
structure of a detected lesion and the surrounding tissue on FFDM. This information is 
particularly important for suggesting the presence of spiculations and the significance of 
calcification distributions. For standard mammography, depth information can be obtained 
only in a very limited way by cognitive merging of information abstracted separately from the 
usual two CC- and MLO-view images of the same breast. 
 
These limitations of FFDM may be significantly reduced through the use of digital breast 
tomosynthesis (DBT), which provides radiologists with in-depth views (through a series of 
cross-sectional views of DBT images) of the internal structure of the breast where each 
reconstructed image contains depth information about breast structure and composition. In 
the DBT examination, each view (CC and MLO) of the breast is acquired as 2D and DBT 
images. The 2D and DBT images are presented for the radiologist’s interpretation on a pair 
of FDA-cleared five-megapixel, grayscale display monitors (see Appendix A).  

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The SenoClaire Digital Breast Tomosynthesis System – PMA Supplement P130020/S001, 
demonstrated 3D digital mammography images suitable to be used in the screening and 
diagnosis of breast cancer.12  
 
Synthesized view (S-View) images are used in the same way that 2D FFDM images are 
used as part of a 3D study, and are generally never viewed independently for screening or 
diagnosis. S-View images are created from a software reconstruction algorithm, allowing for 
reduction in radiation dose, since 2D images do not need to be acquired. S-View images 
can be acquired in any projection and have been shown to be capable of replacing 2D 
FFDM imaging in a 2D/3D combination exam. S-View images can be used when comparing 
to FFDM images, with the diagnosis and BI-RADS assessment made based on the 
combination of the S-View and tomosynthesis images. S-View images are also useful in 
detecting left/right asymmetry as well as in assessing the distributional aspects of 
calcification. If there is a finding in a synthesized image, it will be confirmed with the 
tomosynthesis images.  
 
FFDM with DBT is being replaced by the synthesized 2D mammography with DBT in breast 
imaging to reduce radiation dose while maintaining screening outcomes. Recent clinical 
trials supporting the Selenia Dimensions 3D System (with C-View Module) - PMA 
Supplement: P080003/S001, demonstrated the reasonable assurance of safety and 
effectiveness of DBT plus synthesized 2D technology.6   
 
 

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7. 
Investigational Plan 
7.1. 
Purpose 
The purpose of the pilot reader study is to provide credible performance estimate 
information to properly plan, design, and power the pivotal reader study with respect to:  
 
the radiologists’ performance metrics for the two reading modalities, i.e., FFDM read 
on the ASPIRE Bellus II workstation (“FFDM”), and Synthesized (S-View) read in 
conjunction with DBT on the ASPIRE Bellus II workstation (“DBT plus S-View”) 
 
the magnitude and direction of differences between performance metrics for the two 
modalities; and  
 
variance components and correlations that would influence sample sizes and case 
mix for the pivotal reader study (FMSU2017-002B) comparing performance metrics 
between the two modalities.  
The AUC, sensitivity, specificity, and recall rate are the key performance indices for the 
study analysis. We are particularly interested in performance in the subgroups of biopsy 
benign cases and recall cases, as this will influence case mix for the pivotal reader study. 
7.2. 
Study Endpoints 
All of the following primary, secondary, and additional (optional) endpoints are measured on 
the FFDM read, DBT plus S-View read, and their difference. All measurements require 
correct lesion localization. 
The primary endpoint is: 
 
Non-inferior per-subject average area under the ROC curve (AUC) for DBT plus S-
View versus FFDM, based on per-subject POM scores and requiring correct lesion 
localization 
The secondary endpoints are: 
 
Superior per-subject average AUC for DBT plus S-View versus FFDM 
 
Non-inferior and/or superior per-subject average recall rate for all non-cancer cases 
for DBT plus S-View versus FFDM 
 
Superior per-subject average specificity for DBT plus S-View versus FFDM 
 
Non-inferior and/or superior per-subject average sensitivity for DBT plus S-View 
versus FFDM 
 
Non-inferior per-subject average recall rate for DBT plus S-View versus FFDM for all 
cancer cases 
 
 
7.3. 
Pilot Study Population 
A minimum of 100 cases will be selected from mammograms that were acquired during 
Fujifilm protocol FMSU2013-004A.  
Images to be used in this study were acquired at image-acquisition sites listed in Table 1. 
The sites participated in protocol FMSU2013-004A and acquired images of subjects who 
consented to participate in the study. As part of the consent process, subjects agreed that 

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image data and supporting documentation could be used for future research and 
investigations. 
 
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. Case Reference Standard 
The reference standard for a cancer case is a case in which at least one lesion is 
confirmed as malignant by biopsy or surgery. 
The reference standard for a non-cancer case is biopsy or surgery for benign cases, 
or interpretation by radiologists at the acquisition site for recall and normal cases. 
7.3.2. Sample Size and Case Mix 
Approximately 18 cancer cases and approximately 82 non-cancer cases will be selected 
by the statistician for this pilot reader study from the library of FFDM and DBT 
mammograms collected under Fujifilm protocol FMSU2013-004A. All cancer cases will 
undergo the truthing process described in section 8. The approximately 82 non-cancer 
cases will include:  
 
approximately 17 biopsy benign cases, 
 
approximately 19 recall cases, and 
 
approximately 46 normal cases. 
7.3.3. Inclusion and Exclusion Criteria 
All cases for this pilot MRMC reader study will meet the following eligibility inclusion and 
exclusion criteria (see also Appendix B for inclusion and exclusion criteria from protocol 
FMSU2013-004A). Only subjects who were consented, met all inclusion criteria and 
none of the exclusion criteria, and completed the needed work-up to establish the 
ground truth were considered evaluable. 
 
 

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      Inclusion Criteria 
 
Eligible subjects under protocol FMSU2013-004A, defined as female subjects 
with known true clinical status and 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. 
 
Subjects with unknown clinical status. 
 
Any subject whose positive mammogram was not read during the truthing 
process (see section 8) will not be considered for the pilot reader study.  
 
7.3.4. Case selection and Targeted Distribution 
Cases selected for this study were those that the statistician selected for FMSU2013-
004E and FMSU2013-004F, with the replacement of those cases lost to follow-up or 
otherwise not available for this pilot reader study. Within each category of cancer, 
benign, recall, and normal, cases will be randomly selected to provide the (targeted) 
representative distributions of: 
 
mammographic finding types (Table 2), 
 
breast composition (Table 3),  
 
and equal distribution across acquisition site, to the extent that this can be 
accomplished using cases in the FMSU2013-004A case library.   
Table 2.Targeted distribution of mammographic finding types (approximation) 
Case Type 
Calcification 
Mass 
Total 
Cancer 
8 
10 
18 
Benign biopsy  
7 
10 
17 
Recall  
3 
16 
19 
Normal  
0 
0 
46 
Total 
28 
31 
100 
 
 
 
 
 
 
 

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Table 3.Targeted distribution of mammography breast composition (approximation) 
Breast Tissue Density 
BI-RADS Breast Tissue Composition Category 
Total 
Fatty (50%) 
a - Almost entirely fatty 
10% to 
15% 
b - Scattered areas of fibroglandular density 
40% to 
45% 
Dense (50%) 
c - Heterogeneously dense 
35% to 
40% 
d - Homogeneously dense 
5% to 
10% 
 
Total 
100% 
 
7.4  
Risk/Benefit Assessment 
 
The probable benefits of the device are based on the data that will be collected in the clinical 
study being conducted to support PMA supplement approval. 
 
The ASPIRE Cristalle DBT System is used to reconstruct the breast volume from limited 
angle projections while eliminating the tissue overlapping effects observed in FFDM 
projections. It is likely to benefit a substantial number of screening patients whose cancers 
could have otherwise been missed due to tissue superimposition (false negatives), or who 
may otherwise have been unnecessarily referred for additional workup (false positive). 
 
Synthesized view (S-View) images are created from the reconstructed DBT images. Without 
the need of additional radiation exposure to the patient, the S-View image is generated by 
“combining” the DBT images of that view into a single 2D synthetic mammography image.   
 
The device has no significant risk of direct harm to the patient. 
 
The primary risk of the device comes from the possibility of false positive and false negative 
clinical decisions when using the images produced by the ASPIRE Cristalle DBT System. 
Fujifilm has designed an MRMC study to compare the performance of readers with FFDM 
alone and with DBT plus S-View. The study design is consistent with other mammography 
studies. Because MRMC studies are conducted outside the clinical setting, with an enriched 
case set, and without patient history, the generalizability of some figures of merit such as 
recall rate, sensitivity, and specificity is limited. The design is considered acceptable in order 
to reduce the size of the trial and avoid confounders. 
 
 
 
 
 
 
 
 
 
 
 

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8. 
The Truthing Process 
8.1. 
Purpose 
The purpose of the truthing process will be to determine, for the cancer cases selected by 
the statistician for this pilot reader study, the type of lesion (or finding) visible within the 
mammogram, the location for each lesion (or finding), and the pathology results.  
8.2. 
Qualification Criteria and Training for the Truther 
The truther is a radiologist who meets the expert radiologist eligibility criteria (below), is not 
associated with the diagnosing of cases at the image-acquisition sites (under Fujifilm 
protocol FMSU2013-004A), will not be associated with the reading of images in this pilot 
reader study, and will be available to perform the responsibilities as the study truther and 
conduct the truthing process. 
Base qualification criteria: The base criteria for the truther are as follows: 
 
Board-certified radiologist. 
 
MQSA qualified for both FFDM and tomosynthesis  
 
Experience reading FFDM images on a monitor (softcopy). 
 
Experience reading DBT images on a monitor (softcopy). 
In addition, to merit the designation “expert in breast imaging,” the radiologist selected to be 
the study truther must meet one or more of the following criteria: 
 
Have instructed breast imaging in a professional society meeting.   
 
Have authored textbooks, book chapters, or peer-reviewed journal articles in 
mammography. 
 
Have interpreted mammography for at least 10 years. 
Training: The truther will participate in a training session to ensure understanding of the 
ASPIRE Bellus II workstation, reading DBT plus S-View images, the protocol, the eCRFs, 
study processes, GCP, and the obligations entailed by study participation. Particular 
attention will be given to reviewing the annotation process. 
The study truther will be available as necessary to assist in the conduct of the pilot reader 
study. Possible services to be provided by the study truther include the following: 
 
Conduct of the truthing process (see section 8.3) for this clinical study. 
 
Review of some or all cases selected to be read during a pilot reader study. 
 
Assistance with any clinical questions pertaining to the clinical investigation. 
 
Designation of the location and view(s) in which a finding or findings is/are located. 
The type of lesion (finding) visible within the mammogram and location(s) designated 
and annotated by the truther will be considered as establishing the true type and 
location of the finding(s). 
 
8.3. 
Conduct of the Truthing Process 
8.3.1. Core Reading Center 
Truthing will take place at FUJIFILM Medical Systems, U.S.A., Inc. in Stamford, CT. 
 

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      8.3.2  Preparation of Cases for Truthing 
The study truther may have access to basic information about the subjects including age at 
exam, brief pertinent medical history, BI-RADS descriptors, finding location, and final clinical 
assessment. The anonymity of participating subjects will be maintained. See section 12.6.1 
for detail about maintenance of subject confidentiality, study ID numbers, and tracking. 
Truthing will be performed in a controlled environment with consistent lighting. Using the 
ASPIRE Bellus II workstation, the truther will respectively review the FFDM and DBT plus S-
View images. During the review, the truther will be permitted to use standard softcopy 
imaging tools and all routine post-processing capabilities (for example, magnification and 
windowing/leveling).  
    8.3.3 
Workflow for the Truthing Process 
 
The truther will review all cancer cases selected for inclusion in the reader study.  The 
truther will complete an eCRF for each case, based on materials from the image acquisition 
site including mammograms.  For each cancer case the truther will review the images and 
identify, confirm, and annotate (including the lesion locations and slice, if applicable) for 
each malignant lesion: 
 
The type of lesion visible within the mammogram (mass, microcalcifications 
asymmetric density and/or focal asymmetry) 
 
The breast, view, and if possible the coordinates and slice, if applicable, in which 
each lesion is located 
 
Document the characteristics of the lesion on the eCRF 
 
 

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9. 
Reader Selection and Training 
9.1. 
Purpose 
The purpose of the training process is to ensure that each reader selected for the reading 
session has been adequately trained to read and interpret the DBT plus S-View images on 
the ASPIRE Bellus II workstation.  A radiologist with expertise in digital breast tomosynthesis 
will conduct the training of the radiologists. 
9.2. 
Selection and Qualification Criteria for Readers 
This study will be conducted with radiologists of varying experience levels, from both 
community and academic practices, some of whom have limited experience reading 2D 
synthetic images. These radiologists will not be associated with the acquisition or review of 
cases and did not participate in the truthing process.  
Base qualification criteria: All readers must meet the following base criteria: 
 
Are board-certified  
 
Are MQSA qualified for both FFDM and DBT interpretation 
 
9.3. 
Conduct of the Training Process 
 
The radiologists will receive approximately two hours of training in the evaluation of DBT 
plus S-View images to familiarize them with the S-View images. Training will consist of the 
trainer presenting a brief didactic lecture explaining how synthetic 2D images are generated 
and the differences, advantages and pitfalls compared with digital mammography. The 
trainer will demonstrate how to use and interpret S-View images by presenting selected 
cases to demonstrate the range of typical anatomy, breast density and abnormalities 
identified with DBT. Training will also consist of a hands-on session at the workstation to 
provide the readers with an overview of its DBT-specific functionality. For each view, 
mediolateral oblique (MLO) and cranio-caudal (CC), 2D FFDM and the complimentary S-
View image for the same view will be shown with the DBT images.  The training will also 
emphasize that the S-View images alone will not be used for diagnosis, and scoring will be 
based on the appearance of the lesion on the DBT images.  
 
 
              9.4     Conduct of the Reading Process 
9.4.1     Purpose and Conduct 
The purpose of the reading process is for the readers to provide the BI-RADS assessment 
categories, probability of malignancy (POM) scores, recall scores, locations and types of any 
finding(s) on the eCRFs for their interpretation of the study cases; with FFDM images and 
DBT plus S-View images on the ASPIRE Bellus II workstation. 
 

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Following the successful completion of the reader training, the readers will independently 
review and score each of the image sets of the reader study case set. Each reader will work 
at a designated workstation and will independently perform two reads on all cases. Each 
reader will read each case both as a FFDM read, and a DBT plus S-View read on the 
ASPIRE Bellus II workstation.  Each reader will read half the cases on FFDM and the other 
half of the cases on DBT plus S-View during the first visit.  The reader will then read the 
complimentary FFDM and DBT plus S-View during the second visit. In order to minimize 
memory recall bias, the two reading visits will be separated by a memory washout period of 
approximately four weeks. 
 
Interpretation of mammography images will be performed in a controlled environment with 
consistent lighting. The review workstations will be preloaded with the cases. The readers 
will be permitted to use standard softcopy imaging tools, and all routine post processing 
capabilities (e.g., magnification, windowing and leveling) will be permitted. Hotkeys will be 
provided on the workstations for consistency and accuracy of the reading process. The 
reading time allowed per case will not be limited. A lunch break will be offered during each 
reading session, and radiologists will be encouraged to take a 5-10 minute break each hour, 
as needed. Each reader will dictate their interpretations to a trained scribe, who will enter 
the dictation directly into the eCRF. Each reader will sign an attestation form verifying the 
documented information. 
 
 
9.4.2 Core Reading Center 
 
The reading process with 6 radiologists selected for the pilot reader study will be conducted 
at International HealthCare, LLC in Norwalk, CT. 
 
9.4.3   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 pilot reader study for entry on the eCRFs. 
 
9.4.4 Workflow for the Interpretation of Cases 
 
The readers will be told that the samples of cases do not represent a standard screening 
population, and will be blinded to the actual distribution and nature of the set of images they 
will be asked to review. Readers will be masked to the reference standard and image 
acquisition interpretations (under protocol FMSU2013-004A) for each case. Readers will not 
have access to prior mammograms or other clinical information. All readers will perform their 
interpretations independently. 
 
Each study reader will be randomly assigned to a unique case block (approximately 50% of 
the study cases per block) combination reading order. All study readers will ultimately 
interpret all study cases in both FFDM, and DBT plus S-View formats. Readers will interpret 

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the preloaded mammograms in their assigned randomized order with the use of barcode 
scanner/barcodes.  
General instructions for the readers are as follows: 
 
Do not record single punctuate or round calcifications and vascular calcifications, 
given the high prevalence of these benign findings and their low probability of 
cancer. 
 
Consider all views available from both breasts to determine if you would recall the 
case. 
 
For examinations with multiple findings, record the types and locations of all findings 
in the eCRF and/or a breast schematic diagram that divides each breast image into 
sections and image slice for DBT images. Record the finding locations beginning 
with the most suspicious lesion (up to three lesions per case). 
 
Provide a BI-RADS assessment category in 1 through 5 for each annotated finding.  
 
Provide a probability of malignancy (POM) for each annotated finding according to 
the guidance listed in Table 4 (below).  
Probability of Malignancy (POM): POM is a 0 to 100 score assigned by readers to each 
suspicious finding, as their perception of the percentage chance that the suspicious finding 
might be malignant. To help the assignment of POM scores readers will be instructed to use the 
entire POM scale, with descriptions of POM values provided in Table 4 only as guidance: 
Note: POM scores will be determined and analyzed separately from the BI-RADS assessment 
category. 
 
 
Table 4. Probability of malignancy (POM) guidance 
POM Score (%) 
Description 
0-20 
Negative/Benign  
21–40 
Probably benign 
41–60 
Possibly malignant 
61–80 
Probably malignant 
81–100 
Malignant 
 
Interpretation instructions for the readers are as follows:  
The reader will complete the eCRFs for each case for the two reads. For each case on each 
read, the reader will first record whether there are mammographic findings. If the answer to 
this question is “no” the reader will be asked to confirm for this case: a BI-RADS assessment 

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category of 1 or 2, a POM score following the POM guidance provided in Table 4, and recall 
decision of “no”. If the reader answers “yes” to whether there are mammographic findings, 
the reader will be asked to confirm an initial BI-RADS assessment category of 0, and will 
then provide detailed information on each suspicious finding: 
 
Affected breast (right or left)  
 
Type (includes mass, asymmetry, and/or architectural distortion), microcalcifications, 
or mass with microcalcifications, or other 
 
“Forced” BI-RADS assessment category 1, 2, 3, 4, or 5 
 
POM score 0 through 100 
 
The reader will then be asked whether the case shall be recalled (“yes” or “no”), their 
forced BI-RADS assessment category (1, 2, 3, 4 or 5), and POM score 0 through 
100. 
A study scribe representing the sponsor will capture the radiologist’s results on the eCRFs to 
ensure completeness.  
In cases with mammographic findings, consistency of POM scores with BI-RADS 
assessment categories and recall decisions will not be forced – i.e. readers will be permitted 
to use the full range of POM scores for a finding (following the POM guidance provided in 
Table 4) no matter what BI-RADS assessment category they assign to it. 
 
9.4.5 Reading Sessions with a Memory Washout Period 
Each reader will read each case both as an FFDM read and a DBT plus S-View read, on the 
ASPIRE Bellus II workstation.  Each reader will read half the cases on FFDM and the other 
half of the cases on DBT plus S-View during one visit.  The reader will then read the 
complementary FFDM and DBT plus S-View exams during the second visit.  In order to 
minimize memory recall bias, the two reading visits will be separated by a memory washout 
period of approximately four weeks.   
 
Reading Session Order 
a. 100 cases which were used in prior Fujifilm pilot studies were selected, with 
some updates made due to subjects that did complete the study per protocol, 
etc. The randomization was updated to reflect the replacement cases, and for a 
change in workstation capabilities that will allow use of a worklist rather than 
requiring cases to be loaded on each reader’s workstation in her or his assigned 
interpretation order.  
i. Group A – case number 101 through 200 
ii. Group B – case number 201 through 300 
 
b. Sessions format: 
 
Session 1 
Session 2 
Cases 
Sequence # 
Cases 
Sequence # 
Group A FFDM cases 1501 - 1550 
Group A DBT plus S-
View cases 
2501 - 2550 
Group B DBT plus S-
View cases 
2551 - 2600 
Group B FFDM cases 
1551 - 1600 
 

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c. Reading order within each group will be randomly determined in the beginning 
and will be set for the duration of the reader study. 
d. Each session has 100 cases that will be read – 50 FFDM cases and 50 DBT plus 
S-View cases.   
e. Reading format: 
 
Reader 
Day 1 Read 
Day 31 Read 
Session # 
Sequence 
# 
Session # Sequence # 
Reader #1 
1 
1501-1600 
2 
2501-2600 
Reader #2 
1 
1501-1600 
2 
2501-2600 
Reader #3 
1 
1501-1600 
2 
2501-2600 
Reader #4 
1 
1501-1600 
2 
2501-2600 
Reader #5 
1 
1501-1600 
2 
2501-2600 
Reader #6 
1 
1501-1600 
2 
2501-2600 
 
 
 

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10. The Lesion Matching Process 
10.1 Purpose 
The purpose of the lesion matching process will be to determine if the location and type of a 
finding identified by the reader match those of a malignant lesion annotated by the truther, 
i.e., correct lesion localization and type.  
10.2 Qualification Criteria and Training for the Lesion Matcher 
An expert not associated with diagnosing cases at the image-acquisition sites or serving as 
a reader interpreting images on this pilot reader study will serve as the lesion matcher for 
this study. This expert may be an experienced, MQSA qualified mammography technologist 
with an active license, or a board-certified radiologist that is MQSA qualified for both FFDM 
and tomosynthesis; if the latter, this expert radiologist may be the same person as the 
truther. 
Base qualification criteria: The base criteria for the lesion matcher are as follows: 
 
Has an active license as a breast mammogram technologist 
 
Has experience with clinical research in the GCP environment 
 
Or, Study truther (refer to truther qualifications in section 8.2)   
 
Training: The lesion matcher will participate in a training session to ensure understanding of 
the ASPIRE Bellus workstation, the protocol, the eCRFs, study processes, GCP, and the 
obligations entailed by study participation. Particular attention will be given to the lesion 
matching process. 
10.3 
Conduct of the Lesion Matching Process 
10.3.1 Core Matching Center 
Lesion matching will take place remotely, with results documented within the truther/lesion 
matching database. 
10.3.2 Preparation of Cases for Lesion Matching 
The lesion matcher will have access to both the reader’s eCRF and the truther’s eCRF. The 
eCRF and images contain the annotated information, such as case ID number, the finding 
location(s), and finding type(s) which are required for the determination of correct lesion 
localization. The matching is limited to cases with malignant lesions. For each case with 
cancer, the lesion matcher determines if the annotation by the reader matches with that 
made by the truther.  
 
10.3.3 Workflow for the Lesion Matching Process 
The lesion matching process is limited to those cases with malignant lesions. Based on the 
case ID number on the truther’s eCRF, the lesion matcher identifies the reader’s eCRF with 
the same case ID number. The lesion matcher compares the finding location(s) and finding 
type(s) of the reader’s eCRF and annotated images to those of the truther’s eCRF, to 

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determine if the reader made the correct lesion localization. The process will be repeated for 
each reader’s eCRFs that have the same case ID number as the truther’s eCRFs, and for 
every reader.  The lesion matcher will record the lesion matching results on the eCRFs.  
 
For each truther’s eCRF, identify and confirm the corresponding reader’s eCRF that 
contains the same case ID number 
 
Identify and match the location (breast, view, and if possible the section and/or slice) 
and type of finding(s) with those of the truther’s eCRF 
 
Document the matching results on the eCRF 
Note: To allow for the possibility of lesions located on breast section boundaries, the reader 
will get credit for correctly locating a lesion if the matcher determines that the annotations 
match even if an adjacent quadrant is recorded on the case report form. In this situation, we 
anticipate x/y coordinates to be within 2 centimeters and slice numbers to be within 10 
slices. Readers will not get credit for correctly locating a lesion if the matcher determines 
that the annotations do not match, even if the same quadrant is recorded on the case report 
form; in this situation the x/y coordinates and/or slice numbers also usually would not match 
with the pre-specified tolerance. The lesion matching process will be supported by 
programmatic (computer) determination of whether x and y coordinates are within 2 
centimeters; and whether slice numbers are within 10 slices.  
 

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11. Statistical Analysis 
Study case identification numbers and study reader numbers will be assigned to all cases 
and readers, and used to protect their identities in statistical analysis and in reporting of 
results. All cases will be evaluated the same way by all study readers, i.e., there will be no 
treatment assignments or treatment groups. No interim analyses are planned. No adverse 
events are anticipated on this MRMC study using retrospective cases. Test reproducibility 
will not be evaluated on this MRMC study. The statistician will not be blinded to the review 
setup. 
Baseline descriptive summaries will include the distribution of demographic characteristics and 
type of cancer (soft tissue lesion [mass, asymmetry, architectural distortion, other], 
microcalcification, or soft tissue lesion with microcalcification), lesion size, breast composition 
(BI-RADS breast composition categories) and reference standard status (cancer, benign, recall, 
or normal. We will also provide summaries across readers of the per-subject number of findings, 
BI-RADS scores, POM scores, and per-subject recall scores, for the FFDM and DBT plus S-
View workstation image reviews. These may be cross-classified by, e.g., presence of malignant 
lesions. Categorical variables (such as cancer type and breast tissue composition) will generally 
be summarized using frequencies and proportions or percentages, while continuous variables 
will generally be summarized using means and standard deviations (SDs), or medians and 
quartiles or ranges. Missing values will generally be reported as such in these descriptive 
summaries. 
11.1 
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. 
 
11.2  
Multiple Centers (pooling) 
Fujifilm has obtained images from multiple centers. The protocol for data submission, quality 
review passed by all images, and reference standard status determination for all images used in 
the MRMC study will be common. Cases will be pooled across enrolling centers for interpretation 
on the MRMC study using common interpretation protocol and electronic case report forms 
(eCRFs), and results of interpretation sessions will be monitored. The scoring of (lesion matching 
for) reader interpretations will follow a common process. Results for any particular reader will 
therefore be pooled across enrolling centers. 
11.3 
Derived Variables for Statistical Analyses 
The per-subject BI-RADS score, POM, and recall scores requiring correct lesion localization will 
be derived as in sections 11.3.1 and 11.3.2, respectively. The general principle is that even at 
the subject level, credit is only given for identifying a subject with cancer if the reader marks 
findings in at least one location with cancer. Findings that do not match the location of a 
malignant lesion are ignored for cancer cases in the per-subject analyses but may be reported, 
generally in an appendix.  
When computing sensitivity and specificity based on BI-RADS, a score of 4 or 5 constitutes a 
positive test result. A cutoff score of BI-RADS 3 or higher may also be used to compute the 
sensitivity and specificity in secondary analyses. 
 

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11.3.1 Per-subject scoring: POM and BI-RADS 
The primary endpoint is per-subject AUC based on POM scores requiring correct lesion 
localization. Secondary endpoints include per-breast sensitivity and specificity based on 
BI-RADS categories. Scores for use in this ROC curve analysis and sensitivity and 
specificity analyses will be derived by the statistician as described below and summarized in 
Table 5: 
 
If a case has no proven malignancies: 
 
If the reader does not record any findings in this case: The POM score for this 
case will be the same as the POM score recorded by the reader for the case, 
and the BI-RADS score for this case will be the same as the BI-RADS 
assessment category recorded by the reader for the case.  
 
If the reader records any findings in this case: The reader will dictate POM 
score and BI-RADS assessment category for each (up to 3) lesion. The 
reader will then dictate the overall patient recall determination, to include BI-
RADS assessment category and POM score.  
 
If a case has one or more proven malignancies: 
 
If the reader records one or more findings that are determined by the truther 
to match the location(s) of any proven malignancies in this case: The 
maximum of the POM scores recorded by the reader for those findings will be 
assigned to the case, and the BI-RADS category for the case will be assigned 
as the maximum of the BI-RADS categories recorded by the reader for those 
findings. 
 
If the case contains more than one malignant lesion, the reader will 
get credit for identifying the case as having one or more proven 
malignancies even if the reader does not identify all of the proven 
malignancies in the case. For example, in a bilateral case, the reader 
would get credit for identifying the case even if the reader marks 
findings in only one breast. 
 
If the reader does not record any findings in this case; or when the reader 
records findings in this case, but none of them are determined by the lesion 
matcher to match the location(s) of any proven malignancies: 
 
If the reader did not record any findings in the case, the POM score 
for this case will be the same as the POM score recorded by the 
reader for the case and the BI-RADS score for this case will be the 
same as the BI-RADS assessment category recorded by the reader 
for the case 
 
If the reader recorded one or more findings in this case, but none of 
them are determined by the lesion matcher to match the location(s) of 
any proven malignancies, a POM score of the higher of 0 or, for 
readers who do not assign POM 0 to any case in a reading 
modality, the minimum POM score assigned by that reader in 
that modality will be assigned to the case and the BI-RADS score 
for this case will be assigned as category 1. 

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 
The POM scores and BI-RADS categories for any reader findings in this case 
that do not match the location(s) of any proven malignancies will be ignored 
in the per-subject analysis, which requires a single POM score and single 
BI-RADS category per subject conditional on whether the subject does or 
does not have proven malignancies. 
 
Table 5. Per-subject POM and BI-RADS scores (requiring correct lesion localization) 
 
Reference standard 
Reader’s interpretation 
Per-subject POM and BI-RADS 
No malignancies in this case 
No findings located in this 
case 
POM: Same as POM recorded by the reader for 
the case 
BI-RADS: Same as category recorded by the 
reader for the case 
One or more findings located 
in this case 
POM: Overall POM recorded by the reader for 
the case 
BI-RADS: Overall category recorded by the 
reader for any of those findings 
One or more malignancies in 
this case 
No findings located in this 
case 
POM: Same as POM recorded by the reader for 
the case 
BI-RADS: Same as category recorded by the 
reader for the case 
Findings in this case, but no 
findings matching the 
location(s) of any proven 
malignancies in this case 
POM: Assigned as the higher of zero (0) or, 
for readers who do not assign POM 0 to any 
case in a reading modality, the minimum 
POM score assigned by that reader in that 
modality. 
BI-RADS: Assigned as category one (1) 
One or more findings 
correctly matching the 
location(s) of any proven 
malignancies in this case 
POM: Highest POM score recorded by the 
reader for any of those findings 
BI-RADS: Highest category recorded by the 
reader for any of those findings 
 
 
11.3.2 Per-subject scoring: Recall 
The secondary endpoints include per-subject recall requiring correct lesion localization 
based on a separate yes/no question. Scores for use in these per-subject analyses will be 
derived by the statistician as described below and summarized in Table 6: 
 
If a case has no proven malignancies: 
 
If the reader does not recall the case: The recall score for this case will be the 
same as the recall score recorded by the reader for the case, i.e., no recall.  
 
If the reader recalls the case: The recall score for this case will be the same 
as the recall score recorded by the reader for the case, i.e., recall. 
 
If a case has one or more proven malignancies: 
 
If the reader recalls the case and records one or more findings that are 
determined by the truther to match the location(s) of any proven malignancies 

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in this case: The recall score for this case will be the same as the recall score 
recorded by the reader for the case, i.e., recall. 
 
If the reader does not recall the case; or when the reader recalls the case, but 
none of the reader’s findings are determined by the truther to match the 
location(s) of any proven malignancies: 
 
If the reader did not recall the case, the recall score for this case will be 
the same as the recall score recorded by the reader for the case, i.e., no 
recall. 
 
If the reader recalled the case and recorded one or more findings in 
the case, but none of them are determined by the truther to match the 
location(s) of any proven malignancies, the recall score for this 
case will be assigned as no recall. 
Table 6.  Per-subject recall scores (requiring correct lesion localization) 
Reference standard (truth) 
for this case 
Reader’s interpretation 
Per-subject recall score 
No malignancies 
 
No recall 
Same as recall recorded by the reader 
for the case, i.e., no recall 
Recall 
Same as recall recorded by the reader 
for the case, i.e., recall 
One or more malignancies 
 
No recall 
Same as recall recorded by the reader 
for the case, i.e., no recall 
Recall; Findings in this case, but 
no findings matching the 
location(s) of any proven 
malignancies in this case 
Assigned as no recall 
Recall; One or more findings 
correctly matching the 
location(s) of any proven 
malignancies in this case 
Same as recall recorded by the reader 
for the case, i.e., recall 
 
11.3.3 True Positive, False Negative, True Negative, and False Positive 
In per-subject analysis: 
 
A true positive (TP) occurs when a case contains one or more cancerous lesions, and 
the per-subject BI-RADS score is 4, or 5. This happens when the reader marks one or 
more findings, at least one of those findings matches the location of one or more 
cancerous lesions, and the reader assigns a BI-RADS category 4 or 5 to at least one 
such finding. 
 
A false negative (FN) occurs when a case contains one or more cancerous lesions, and 
the per-subject BI-RADS score is 1, 2, or 3. This happens when either: 1) the reader 
does not mark any findings that match the location of one or more cancerous lesions, or 
2) the reader marks one or more findings, at least one of those findings matches the 
location of one or more cancerous lesions, but none of the scores assigned to those 
findings are higher than BI-RADS 3. 

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 
A true negative (TN) occurs when a case does not have any cancerous lesions, and the 
per-subject BI-RADS score is 1, 2, or 3. This happens when either: 1) the reader does 
not mark any findings in the case, or 2) the reader marks one or more findings in the 
case, but none are higher than BI-RADS 3. 
 
A false positive (FP) occurs when a case does not have any cancerous lesions, and the 
per-subject BI-RADS score is 4, or 5. This happens when the reader marks findings in a 
case containing no cancerous lesions, and assigns a BI-RADS category 4 or 5 to at 
least one such finding. 
When computing recall rates requiring correct lesion localization, a recall occurs when a 
case has per-subject recall score equal to yes. This happens whenever the reader recalls a 
non-cancer case; or when the reader recalls a cancer case and marks one or more findings 
and at least one of those findings matches the location of one or more cancerous lesions. 
 
 
11.4 
Analysis of Primary Endpoint 
The primary endpoint on this study is per-subject AUC requiring correct lesion localization. We 
will estimate AUCs for each reader in each review condition (FFDM, DBT plus S-View) based 
on per-subject POM scores. These POM scores will require correct lesion localization, such that 
in a subject with cancer if the reader recorded one or more findings in the case but no findings 
are determined by the lesion matcher to match the location(s) of any proven malignancies, a 
POM score of 0 or, for readers who do not assign POM 0 to any case in a reading modality, the 
minimum POM score assigned by that reader in that modality, will be assigned to the breast 
(section 11.3.1). 
Primary analysis will not involve pooling across study radiologists, to allow for heterogeneity 
among them. We will provide graphs of each reader’s ROC curve for each review condition. 
For each reader, the non-parametric (trapezoidal) AUC for the FFDM read, the DBT plus 
S-View read, and the difference between them, will be presented. Statistical inferences will 
account for correlations arising from having all study readers interpret all study cases. We 
plan to perform MRMC comparison of AUCs between FFDM and DBT plus S-View using the 
standard MRMC analysis of variance (ANOVA) method of Obuchowski and Rockette 
(1995)11 to ensure generalization of the study results both to the population of readers and 
the population of cases. Two-sided 95% confidence intervals (CIs) will be used to quantify 
uncertainty in the within-modality estimates and the between-modalities difference. 
The magnitude and direction of differences between performance metrics for the two 
modalities, and variance components and correlations that would influence sample sizes 
and case mix for the pivotal reader study (FMSU2017-002B) comparing performance 
metrics between the two modalities, will be obtained from this MRMC analysis. 
 
11.5 
Analysis of Secondary Endpoints 
The following secondary endpoints will be explored in this pilot study, in order to best plan 
for the secondary endpoints for the pivotal study. When analyzing secondary aims per-
subject recall, BI-RADS, and POM scores requiring correct lesion localization will be derived 
as described in 11.3.1 and 11.3.2. Two-sided 95% CIs will be used to quantify uncertainty. 
1. Superior per-subject average AUC for DBT plus S-View versus FFDM, based on 
POM scores and requiring correct lesion localization. 

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Analysis will be performed similarly to analysis of the Primary Aim.  
2. Non-inferior and/or superior (lower) per-subject average recall rate for all non-cancer 
cases for DBT plus S-View versus FFDM, based on recall scores, using non-
inferiority margin delta = 0.05. 
Analysis of per-subject recall rates for all non-cancer cases will be performed using 
standard MRMC analysis of variance (ANOVA) methods described in Obuchowski 
and Rockette (1995)13 
3. Superior per-subject average specificity for DBT plus S-View versus FFDM, based 
on BI-RADS scores. 
Analysis of per-subject specificity is limited to the subgroup of subjects without 
cancer. This analysis also will use the MRMC method of Obuchowski and Rockette 
(1995)13 
4. Non-inferior and/or superior per-subject average sensitivity for DBT plus S-View 
versus FFDM, based on BI-RADS scores requiring correct lesion localization, using 
non-inferiority margin delta = 0.10. 
Analysis of per-subject sensitivity is limited to the subgroup of subjects with cancer. 
This analysis will be performed similarly to analysis of per-subject specificity. 
5. Non-inferior per-subject average recall rate for DBT plus S-View versus FFDM for all 
cancer cases, based on recall score, using non-inferiority margin delta = 0.10. 
Analysis of per-subject recall rate for all cancer cases will be performed similarly to 
analysis of per-subject recall rates for all non-cancer cases. 
 
12. Sponsor and Investigational Site Requirements (Study Administration) 
12.1 
Ethics 
12.1.1 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.  
 
12.1.2 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. 
 
12.2 
Reader Informed Consent 
Each reader must provide written informed consent before participating in the reader study 
of this protocol. 
 
12.3 
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. 
12.3.1 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 reconsent 
subjects already enrolled in the study, if they are affected by the amendment. 
 
12.4 
Retention of Study Records 
All documents pertaining to the conduct of this clinical study – including eCRFs, 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 

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investigator must contact the sponsor to arrange for transfer of responsibilities and 
alternative record storage options, if applicable. 
Study documentation includes all eCRFs, 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. Source documents include but are not limited to tissue diagnosis 
reports, mammography images, subject progress notes, hospital charts, appointment books, 
radiology reports, and any other records or reports of procedures performed during the 
study. 
 
12.5 
Data Collection and Management 
12.5.1 General 
All data entry will be performed using an eDC system following the guidelines 
established in a Data Entry Guidelines document. An eDC Training & Registration form 
will be kept for all study site personnel which will include date of training, participant 
contact information, and eDC user privilege level. Training will include review of all study 
specific guidelines and data entry requirements.  
The privacy of participating subjects must be maintained in accordance with the HIPAA 
privacy ruling and disclosed per 24CFR50. 
The eCRFs will be data entered, and then reviewed for accuracy and completeness by a 
study monitor representing Fujifilm, as well as reviewed by DMC staff.  
12.5.2 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. 
Electronic CRFs will be logged and tracked when received by the DMC. eCRFs 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. 
12.5.3 New Suspicious Findings 
If half or more of the study readers note a suspicious finding (BI-RADS 0, 3, 4 or 5) not 
documented by the image acquisition facility, the DMC will write a letter to the principal 
investigator at the image acquisition site noting the finding. 
 
 
 
 

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12.6 
Confidentiality 
12.6.1 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 (that is, a unique number for 
each DBT plus S-View case and a different unique number for each FFDM case) will be 
assigned to each subject 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. 
12.6.2 Reader Confidentiality 
Information collected during the pilot 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 pilot reader study for entry on the eCRF’s. A master list of these ID numbers for the 
radiologists participating in the pilot reader study will be securely maintained by the 
Fujifilm project manager. 
12.6.3 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).  
 
12.7 
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 eCRF 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). 
12.8 
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. 
 

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12.9 
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. 
12.10 
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 primary investigator, truther, lesion matcher and pilot 
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. 
12.11 
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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13 
References 
1. American Cancer Society. How common is breast cancer? Available at: 
https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html 
Accessed July 25, 2017. 
 
2. American Cancer Society. Detailed guide: Breast cancer. What are the risk factors for 
breast cancer? Available at: 
http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-risk-factors. 
Accessed September 22, 2013. 
3. Nelson HD, Tyne K, Naik A, et al. Screening for breast cancer: an update for the U.S. 
Preventive Services Task Force. Ann Intern Med. 2009;151:727-737. 
4. U.S. Preventive Services Task Force. Screening for Breast Cancer: U.S. Preventive 
Services Task Force Recommendation Statement. Ann Intern Med. 2009;151:716-726. 
Available at: http://www.ahrq.gov/clinic/uspstf09/breastcancer/brcanrs.pdf. Accessed 
February 3, 2009. 
5. Hellquist BN, Duffy SW, Abdsaleh S, et al. Effectiveness of population-based service 
screening with mammography for women ages 40 to 49 years: evaluation of the 
Swedish Mammography Screening in Young Women (SCRY) cohort. Cancer. 2011 Feb 
115; 117(4); 714-22. doi: 10.1002/cncr.25650 
6. Selenia Dimensions 3D System –Summary of Safety and Effectiveness Data (SSED) for 
P080003 (September 24, 2010) and P080003/S001 (October 24, 2012). 
7. Sickles EA, Wolverton DE, Dee KE. Performance parameters for screening and 
diagnostic mammography: specialist and general radiologists. Radiology. 2002; 
224:861-869. 
8. Sickles EA, Miglioretti DL, Ballard-Barbash R, et al. Performance benchmarks for 
diagnostic mammography. Radiology. 2005; 235:775-790. 
9. National Cancer Institute. Breast Cancer Surveillance Consortium data. Available at: 
http://breastscreening.cancer.gov/data/variables/. Accessed July 14, 2017. 
10. Warner, E.  Breast-Cancer Screening. The New England Journal of Medicine. 
2011,365:1025-1032. 
11. Obuchowski NA, Rockette HE. Hypothesis testing of diagnostic accuracy for multiple 
readers and multiple tests: an ANOVA approach with dependent observations. 
Communications in Statistics - Simulations. 1995; 24(2): 285-308. 
12. SenoClaire DBT Option to Senographe Essential FFDM System – Summary of Safety 
and Effectiveness Data (SSED) for P130020 (August 26, 2014) and P130020/S001 
(January 5, 2017). 
13. Obuchowski RA, Lieber, ML, Powell, KA. Data analysis for detection and localization of 
multiple abnormalities with application to mammography. Acad. Radiol. 2000; 7: 516-
525. 
 
 

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14 
Appendices 
Appendix A: Fujifilm FFDM and DBT Image Acquisition, Display, and Interpretation 
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 with S-View (Figure B) mammography acquisition 
system generates both FFDM and DBT images. It is comprised of the X-ray exposure unit and 
acquisition workstation, which is FDA PMA approved (P260031) for mammography and digital 
breast tomosynthesis image acquisition. S-View images are created from the reconstructed DBT 
images. Without the need of additional radiation exposure to the patient, the S-View image is 
generated by “combining” the DBT images of that view into a single 2D synthetic mammography 
image.  The S-View image, which may look similar to a FFDM image, is automatically labeled as 
“S-View” to avoid confusion with the FFDM image. 
Fujifilm’s ASPIRE Bellus II (Figure C) mammography review workstation displays and supports 
the physician’s review of 2D mammography, DBT and S-View images. It is comprised of the 
display accessories of the ASPIRE Cristalle that include the major components of a PC (with 
image review and manipulation software installed), a console monitor, and two high-resolution 
grayscale diagnostic display monitors. 
 
 
 
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 plus S-View Images by ASPIRE Cristalle DBT Option 
(Figure A) 
All FFDM and DBT plus S-View images of the enrolled study subjects were acquired on the 
ASPIRE Cristalle system. 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.  
The DBT images will be acquired first and then the x-ray tube will return to the normal in 
relation to the detector and the FFDM image will be acquired. The S-View images will be 
reconstructed by the acquisition workstation (AWS) of the ASPIRE Cristalle system. 
Display of FFDM and DBT plus S-View 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. 
Each CC and MLO view of the breast can be seen as a single FFDM image or a DBT plus 
Acquisition 
Workstation 
Exposure Unit 
Viewer 
Console 
PC 

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S-View images. The viewer supports typical image-manipulation functions, such as 
windowing-and-leveling, zooming, etc. 
Reading FFDM and DBT plus S-View Mammograms 
 
Reading DBT plus S-View examination follows the traditional image-review process in 
FFDM examination except that the physician will read the DBT plus S-View images instead 
of a single FFDM image for each of the CC and MLO views of the breast. During the 
reading, the physician can control many aspects of the displayed images and hanging 
protocol(s). 
 
 

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Appendix B: Inclusion and Exclusion Criteria from FMSU2013-004A, Version 3.0 
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 of 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. 

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 
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)