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 Pivotal Study
Conditions: Breast Cancer
Sponsor: Fujifilm Medical Systems USA, Inc.

FUJIFILM Medical Systems U.S.A., Inc. 
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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 
 
 
 
 
 
 
 
 
 
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 Acceptance of this document constitutes agreement by the recipient that no unpublished 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 ...................................................................... 18 
5. 
Investigators and Study Administrative Structure ........................................................ 19 
6. 
Background and Rationale .............................................................................................. 20 
7. 
Investigational Plan ......................................................................................................... 22 
7.1. 
Purpose ..................................................................................................................... 22 
7.2. 
Study Endpoints ....................................................................................................... 23 
7.3. 
Pivotal Study Population .......................................................................................... 24 
7.3.1. 
Case Reference Standard.................................................................................... 24 
7.3.2. 
Sample Size and Case Mix .................................................................................. 24 
7.3.3. 
Inclusion and Exclusion Criteria ........................................................................... 25 
7.3.4. 
Case selection and Targeted Distribution ............................................................. 25 
     7.4     Risk/Benefit Assessment……………………………………………………………...….26    
8. 
The Truthing Process ...................................................................................................... 28 
8.1. 
Purpose ..................................................................................................................... 28 
8.2. 
Qualification Criteria and Training for the Truther ................................................. 28 
8.3. 
Conduct of the Truthing Process ............................................................................ 28 
8.3.1. 
Core Reading Center ........................................................................................... 28 
8.3.2. 
Preparation of Cases for Truthing ........................................................................ 29 
8.3.3. 
Workflow for the Truthing Process ....................................................................... 29 
9. 
Reader Selection and Training ........................................................................................ 30 
9.1. 
Purpose ..................................................................................................................... 30 
9.2. 
Selection and Qualification Criteria for Readers .................................................... 30 
9.3. 
Conduct of the Training Process ............................................................................. 30 
10. The Reading  Process ...................................................................................................... 31 
10.1. 
Purpose .................................................................................................................. 31 
10.2. 
Conduct of the Reading Process ......................................................................... 31 
10.2.1. 
Core Reading Center ....................................................................................... 31 
10.2.2. 
Preparation of Cases for Interpretation ............................................................. 31 
10.2.3. 
Workflow for the Interpretation of Cases ........................................................... 31 
10.2.4. 
Reading Sessions with a Memory Washout Period .......................................... 33 
11. The Lesion Matching Process ......................................................................................... 35 
11.1. 
Purpose .................................................................................................................. 35 
11.2. 
Qualification Criteria and Training for the Lesion Matcher ................................ 35 
11.3. 
Conduct of the Lesion Matching Process ........................................................... 35 

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11.3.1. 
Core Matching Center ...................................................................................... 35 
11.3.2. 
Preparation of Cases for Lesion Matching ........................................................ 35 
11.3.3. 
Workflow for the Lesion Matching Process ....................................................... 35 
12. Statistical Analysis .......................................................................................................... 37 
12.1 
Analysis Set .............................................................................................................. 37 
12.2 
Multiple Centers (pooling) ........................................................................................ 37 
12.3 
Derived Variables for Statistical Analyses .............................................................. 37 
12.3.1 
Per-subject scoring: POM and BI-RADS .............................................................. 38 
12.3.2 
Per-subject scoring: Recall .................................................................................. 39 
12.3.3 
True Positive, False Negative, True Negative, and False Positive ....................... 40 
12.4 
Subgroups ................................................................................................................. 41 
12.5 
Analysis of Primary Endpoint .................................................................................. 41 
12.6 
Analysis of Secondary Endpoints ........................................................................... 42 
12.7 
Sample Size Calculations ......................................................................................... 45 
13 Sponsor and Investigational Site Requirements (Study Administration) .................... 47 
13.1 
Ethics ......................................................................................................................... 47 
13.1.1 
Ethical Conduct of the Study ................................................................................ 47 
13.1.2 
Institutional Review Board.................................................................................... 47 
13.2 
Reader Informed Consent ........................................................................................ 48 
13.3 
Protocol Compliance ................................................................................................ 48 
13.3.1 
Protocol Amendments .......................................................................................... 48 
13.4 
Retention of Study Records ..................................................................................... 48 
13.5 
Data Collection and Management ............................................................................ 49 
13.5.1 
General ................................................................................................................ 49 
13.5.2 
Data Management Center .................................................................................... 49 
13.5.3 
New Suspicious Findings ..................................................................................... 49 
13.6 
Confidentiality ........................................................................................................... 50 
13.6.1 
Subject Confidentiality ......................................................................................... 50 
13.6.2 
Reader Confidentiality .......................................................................................... 50 
13.6.3 
Transfer of Confidential Information to the Sponsor or the DMC .......................... 50 
13.7 
Study Monitoring ...................................................................................................... 50 
13.8 
Sponsor Audits ......................................................................................................... 50 
13.9 
Inspection by a Regulatory Agency ......................................................................... 51 
13.10 
Financial Disclosure.............................................................................................. 51 
13.11 
Study or Study-site Termination .......................................................................... 51 
14 References........................................................................................................................ 52 
15 Appendices....................................................................................................................... 54 
Appendix A: Fujifilm FFDM and DBT Image Acquisition, Display, and Interpretation .... 54 
Appendix B: Inclusion and Exclusion Criteria from FMSU2013-004A, Version 3.0 ......... 56 
Inclusion Criteria/Exclusion Criteria .................................................................................... 56 

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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 
IRB 
Institutional Review Board 

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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 standard 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 
Fujifilm Mammography Viewer. 
FFDM Images 
Standard 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 Fujifilm Mammography 
Viewer (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 
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 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 

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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 
for Cancer Cases 
Biopsy or surgery: At least one lesion is confirmed as malignant by biopsy or surgery. 
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 

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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 ......................................................24 
Table 2: Targeted distribution of mammographic finding types (approximation) ........................26 
Table 3: Targeted distribution of mammography breast composition (approximation) ...............26 
Table 4: Probability of malignancy (POM) guidance ..................................................................33 
Table 5: One Possible Experimental Design .............................................................................34 
Table 6:  Per-subject POM and BI-RADS scores requiring correct lesion location .....................39  
Table 7: Per-subject recall scores (requiring correct lesion localization) ....................................40 
Table 8: Hypotheses to be tested ..............................................................................................44  
Table 9: Estimated Power for Primary Endpoint: Non-inferior AUC ...........................................47  
 
 
 
Figure A. One example of a graphical method to control study type 1 error rate………………..45 
Figure B. ASPIRE Cristalle .......................................................................................................54 
Figure C. ASPIRE Bellus II .......................................................................................................54 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 Pivotal Study 
Protocol Number 
FMSU2017-002B 
Effective Date  
March 13, 2018 
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 
 
 
 
 
Robert A. Uzenoff 
Executive Director, Clinical Science
April 3, 2018

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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 Pivotal Study 
Protocol Number 
FMSU2017-002B 
Effective Date  
March 13, 2018 
Study Sponsor 
FUJIFILM Medical Systems U.S.A., Inc. 
419 West Avenue 
Stamford, Connecticut 06902, U.S.A. 
Principal Investigator 
Laurie L. Fajardo, M.D., MBA, FACR, FSBI 
Radiology Consultant 
1730 Lucky John Dr. 
Park City, UT 84060 
 
 
 
I, the principal 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. 
 
Principal Investigator 
 
Signature 
 
Date 
 
 
 
 
Laurie L Fajardo, MD, MBA, FACR, FSBI
April 3, 2018

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3. 
Protocol Synopsis 
SPONSOR NAME 
FUJIFILM Medical Systems U.S.A., Inc. 
PROTOCOL NUMBER 
FMSU2017-002B 
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 Pivotal Study 
DEVICE NAME 
Fujifilm ASPIRE Cristalle with DBT Option 
PURPOSE 
The purpose of the pivotal reader study is to assess the comparative accuracy of 
Fujifilm DBT plus S-View versus FFDM in the detection of breast cancer. Radiologists’ 
performance metrics for the following modalities will be evaluated: 
1. Standard FFDM read on the ASPIRE Bellus II workstation (“FFDM”) 
2. Synthesized (S-View) read in conjunction with DBT read on the ASPIRE 
Bellus II workstation (“DBT plus S-View”) 
This retrospective, multi-reader multi-case (MRMC) study will have an enriched 
sample of approximately 300 cases: 60 cancer cases and 240 non-cancer cases 
(including up to 48 biopsy proven benign cases and 72 recall cases). Enrichment is 
with respect to proportions of cancer cases, biopsy benign cases, and recall cases. 
As its primary endpoint, this study is designed to evaluate whether the area under the 
receiver operating characteristic (ROC) curve (AUC) based on probability of 
malignancy (POM) scores and requiring correct lesion localization is statistically 
significantly non-inferior for DBT plus S-View versus FFDM. Multiple secondary 
endpoints are outlined in the next section.    
STUDY ENDPOINTS 
 
The safety and effectiveness of DBT plus S-View are both linked to the ability of 
radiologists interpreting DBT plus S-View images to accurately diagnose breast 
cancer. Each study endpoint therefore addresses both safety and effectiveness. 
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 POM scores and requiring 
correct lesion localization 
The study will be considered to have successfully demonstrated safety and 
effectiveness of the Fujifilm ASPIRE Cristalle DBT plus S-View system if the per-
subject average AUC for DBT plus S-View is statistically significantly non-inferior 
to the average AUC for FFDM at the alpha = 0.05 significance level, for non-
inferiority margin delta = 0.05. This will be established if the lower limit of the two-
sided 95% CI for the difference in average AUC for DBT plus S-View – FFDM lies 
entirely above –0.05. 
 

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The secondary endpoints are: 
 
1. 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. 
2. 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 
3. 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 
4. Superior per-subject average AUC for DBT plus S-View versus FFDM, 
based on POM scores and requiring correct lesion localization 
5. Non-inferior and/or superior per-subject average specificity for DBT plus 
S-View versus FFDM, based on BI-RADS scores 
6. Superior (lower) per-subject average recall rate for DBT plus S-View 
versus FFDM for all follow-up proven non-cancer recall cases 
7. Non-inferior per-lesion average sensitivity for masses, masses with 
calcifications, focal asymmetries, and/or architectural distortions for DBT 
plus S-View versus FFDM, based on BI-RADS scores requiring correct 
lesion localization, using non-inferiority margin delta = 0.10 
8. Non-inferior and/or superior per-lesion average sensitivity for calcifications 
for DBT plus S-View versus FFDM, based on BI-RADS scores requiring 
correct lesion localization, using non-inferiority margin delta = 0.10 
9. Non-inferior (margin delta = 0.05 for AUC, 0.10 for other performance 
metrics) and/or superior average AUC and/or other performance metric(s) 
for DBT plus S-View versus FFDM for subjects with dense breasts (BI-
RADS breast composition categories c. The breasts are heterogeneously 
dense, which may obscure small masses and d. The breasts are 
extremely dense, which lowers the sensitivity of mammography) 
CORE READING CENTER 
The pivotal study will be performed at International HealthCare, LLC in Norwalk, CT. 
PRINCIPAL INVESTIGATOR, 
TRUTHER, READERS, AND 
LESION MATCHER 
The principal investigator for this study is Laurie Fajardo, MD, MBA, FACR, FSBI. 
The truther, the lesion matcher, and the pivotal study radiologist readers shall meet all 
criteria for their respective roles as specified in the investigational plan.  
The truther, the lesion matcher, and the pivotal 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. 
 
PIVOTAL READER STUDY 
POPULATION 
- SAMPLE SIZE AND CASE 
MIX 
- CASE SELECTION AND 
TARGETED DISTRIBUTION 
 
This clinical research is a retrospective, pivotal, multi-reader, multi-case (MRMC) 
study with an enriched sample of 300 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 

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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 include assignment of study 
and reader unique ID numbers. 
1.  Sample Size and Case Mix 
Enriched sample size of approximately 300 cases (approximately 60 cancer cases 
and approximately 240 non-cancer cases) with the following case mix: 
 
Approximately 60 cancer cases, 48 biopsy benign cases, 72 recall cases, 
and 120 normal cases. 
2.  Case Selection and Targeted Distribution 
The statistician will select cases for this pivotal reader study and cases will be 
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, pivotal, multi-reader, multi-case (MRMC) 
study with an enriched sample of approximately 60 cancer cases and approximately 
240 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 
normal cases. 
1. 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 
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2. The Reading Process 
Approximately 18 qualified radiologists will independently perform two reads on 
all (approximately 300) cases. Each reader will read each case both as a FFDM 
read and a DBT plus S-View read, all 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 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 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. 
 
3. 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 of the 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. 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.  
1.2. 
Analysis of secondary endpoint(s) 
Analysis of per-subject recall rates, specificity, and/or sensitivity will use standard 
MRMC ANOVA methods. Analysis of per-lesion sensitivity will use methods for 
clustered data from MRMC studies that take into account the correlation between 

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lesions in the same case. Subgroup analyses in non-cancer case types, lesion 
types, and/or breast density cohorts will use similar methods. 
1.3. 
Multiple Comparisons 
To protect the study’s type I error rate from inflation we will use the iterative 
graphical approach described in Bretz, et al. (2009)13 to sequentially reject 
hypotheses.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 FMSU2017-002B 
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 
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 

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5.  Investigators and Study Administrative Structure 
Study Personnel 
Principal Investigator 
 
Laurie L. Fajardo, MD, 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: 301.251.992 
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 2018 about 
266,120 new cases of invasive breast cancer and about 63,960 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 2018, about 40,920 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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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, and the SenoClaire Digital Breast Tomosynthesis System (with 
V-Preview) – PMA Supplement P130020/S001, demonstrated 3D digital mammography 
images suitable to be used in the screening and diagnosis of breast cancer as well as the 
reasonable assurance of safety and effectiveness of DBT plus synthesized 2D 
technology.16,18  
 
 
 
 

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7. Investigational Plan 
7.1 
Purpose 
The purpose of the pivotal reader study is to evaluate the comparative accuracy of Fujifilm 
DBT plus S-View versus FFDM in the detection of breast cancer.  The radiologists’ 
performance metrics for the following modalities will be evaluated: 
 
FFDM read on the ASPIRE Bellus II workstation (“FFDM”) 
 
Synthesized (S-View) read in conjunction with DBT on the ASPIRE Bellus II 
workstation (“DBT plus S-View”) 
This retrospective, multi-reader multi-case (MRMC) study will have an enriched sample of 
approximately 300 cases: 60 cancer cases and 240 non-cancer cases (including up to 48 
biopsy proven benign cases and 72 recall cases). Enrichment is with respect to proportions 
of cancer cases, biopsy benign cases, and recall cases. 
As its primary endpoint, this study is designed to evaluate whether the area under the 
receiver operating characteristic (ROC) curve (AUC) based on probability of malignancy 
(POM) scores and requiring correct lesion localization is statistically significantly non-inferior 
for DBT plus S-View versus FFDM. Among its secondary endpoints, the study is designed to 
evaluate: 
1. 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. 
2. 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 
3. 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 
4. Superior per-subject average AUC for DBT plus S-View versus FFDM, based on 
POM scores and requiring correct lesion localization 
5. Non-inferior and/or superior per-subject average specificity for DBT plus S-View 
versus FFDM, based on BI-RADS scores 
6. Superior (lower) per-subject average recall rate for DBT plus S-View versus FFDM 
for all follow-up proven non-cancer recall cases 
7. Non-inferior per-lesion average sensitivity for masses, masses with calcifications, 
focal asymmetries, and/or architectural distortions for DBT plus S-View versus 
FFDM, based on BI-RADS scores requiring correct lesion localization, using non-
inferiority margin delta = 0.10 
8. Non-inferior and/or superior per-lesion average sensitivity for calcifications for DBT 
plus S-View versus FFDM, based on BI-RADS scores requiring correct lesion 
localization, using non-inferiority margin delta = 0.10 
9. Non-inferior (margin delta = 0.05 for AUC, 0.10 for other performance metrics) and/or 
superior average AUC and/or other performance metric(s) for DBT plus S-View 
versus FFDM for subjects with dense breasts (BI-RADS breast composition 
categories c. The breasts are heterogeneously dense, which may obscure small 

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masses and d. The breasts are extremely dense, which lowers the sensitivity of 
mammography) 
7.2 Study Endpoints 
The safety and effectiveness of DBT plus S-View are both linked to the ability of radiologists 
interpreting DBT plus S-View images to accurately diagnose breast cancer. Each study 
endpoint therefore addresses both safety and effectiveness. 
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 POM scores and requiring correct lesion localization 
The study will be considered to have successfully demonstrated safety and effectiveness of 
the Fujifilm ASPIRE Cristalle DBT plus S-View system if the per-subject average AUC for 
DBT plus S-View is statistically significantly non-inferior to the average AUC for FFDM at the 
alpha = 0.05 significance level, for non-inferiority margin delta = 0.05. This will be 
established if the lower limit of the two-sided 95% CI for the difference in average AUC for 
DBT plus S-View – FFDM lies entirely above –0.05. 
The secondary endpoints are: 
1. 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. 
2. 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 
3. 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 
4. Superior per-subject average AUC for DBT plus S-View versus FFDM, based on 
POM scores and requiring correct lesion localization 
5. Non-inferior and/or superior per-subject average specificity for DBT plus S-View 
versus FFDM, based on BI-RADS scores 
6. Superior (lower) per-subject average recall rate for DBT plus S-View versus FFDM 
for all follow-up proven non-cancer recall cases 
7. Non-inferior per-lesion average sensitivity for masses, masses with calcifications, 
focal asymmetries, and/or architectural distortions for DBT plus S-View versus 
FFDM, based on BI-RADS scores requiring correct lesion localization, using non-
inferiority margin delta = 0.10 
8. Non-inferior and/or superior per-lesion average sensitivity for calcifications for DBT 
plus S-View versus FFDM, based on BI-RADS scores requiring correct lesion 
localization, using non-inferiority margin delta = 0.10 
9. Non-inferior (margin delta = 0.05 for AUC, 0.10 for other performance metrics) and/or 
superior average AUC and/or other performance metric(s) for DBT plus S-View 
versus FFDM for subjects with dense breasts (BI-RADS breast composition 
categories c. The breasts are heterogeneously dense, which may obscure small 

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masses and d. The breasts are extremely dense, which lowers the sensitivity of 
mammography) 
 
Multiple Comparisons. To protect the study’s type I error rate from inflation we will use the 
iterative graphical approach described in Bretz, et al. (2009) to sequentially reject 
hypotheses.13 
 
7.3 
Pivotal Study Population 
A minimum of 300 cases (60 cancer cases and 240 non-cancer 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 that study. As part of the consent process, subjects agreed that 
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 

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Approximately 60 cancer cases and approximately 240 non-cancer cases will be 
selected by the statistician for this pivotal reader study from the library of FFDM and 
DBT mammograms collected under protocol FMSU2013-004A. All cancer cases will 
undergo the truthing process described in section 8. The approximately 240 non-cancer 
cases will include:  
 
approximately 48 biopsy benign cases 
 
approximately 72 recall cases 
 
approximately 120 normal cases 
 
7.3.3 Inclusion and Exclusion Criteria 
 
All cases for this pivotal 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. 
 
 
      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 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 pivotal MRMC reader 
study.  
 
7.3.4 Case selection and Targeted Distribution 
Cases 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.  
The statistician may provide a backup list of cases to be used in the event that, e.g., 
imaging files are not available for the reader study. 

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Table 2:  Targeted distribution of mammographic finding types (approximation) 
Case Type 
Calcification (incl. 
calcification w/ Mass) 
Mass  
(non 
calcification) 
No 
Findings 
Total 
Cancer 
10% 
10% 
 
20% 
Benign 
8% 
8% 
 
16% 
Recall 
12% 
12% 
 
24% 
Normal 
0 
0 
40% 
40% 
Total 
30% 
30% 
40% 
100% 
 
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 Fibroglandular 
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 

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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 pivotal 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 pivotal 
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 in 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 pivotal 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 pivotal 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 findings. 
 
8.3 Conduct of the Truthing Process 
8.3.1 Core Reading Center 
Truthing will take place at International HealthCare, LLC in Norwalk, 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 will have had no experience reading 
synthesized (S-View) images. These radiologists will not be associated with the acquisition 
or review of cases and did not participate in the truthing process. A survey questionnaire will 
be sent to prospective readers to determine the fraction of their professional time devoted to 
breast imaging. Approximately 18 board certified radiologists, MQSA qualified in 
tomosynthesis and FFDM and with a range of experience based on the volume of cases 
read per year, will be selected to read and score the study images.  
Case volume will be categorized into three groups:  
 
 
High Volume Reader - defined as radiologists who read more than 5000 
mammograms per year.  
 
Medium Volume Reader - defined as radiologists who read more than 3000 up to 
5000 mammograms per year.  
 
Low Volume Reader - defined as radiologists who read 3000 or fewer 
mammograms per year.  
 
 
Base qualification criteria: All readers must meet all of 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 three 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 corresponding 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.  

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10. The Reading Process 
10.1 
Purpose 
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. 
10.2 
Conduct of the Reading Process 
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 
complementary 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. 
 
10.2.1 Core Reading Center 
 
The reading process will be conducted at International HealthCare, LLC in Norwalk, CT. 
 
10.2.2 Preparation of Cases for Interpretation 
 
To maintain subject confidentiality, no identifying subject data will be displayed. Unique 
image identifiers associated with the case ID number will be visible on each image for 
tracking purposes. To maintain reader confidentiality, a unique ID number will be assigned 
to each radiologist participating in the pivotal reader study for entry on the CRFs. 
Information collected during the research study was reported in such a way that it precluded 
identification of any image acquisition centers’ or study radiologists’ performance. 
 

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10.2.3 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 reading order. All study readers 
will ultimately interpret all study cases in both FFDM, and DBT plus S-View formats. 
Readers will interpret the preloaded mammograms in their assigned 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 of 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. 
 
 
 
 
 
 

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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 
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. 
 
10.2.4 Reading Sessions with a Memory Washout Period 
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 
complementary 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.   

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Reading Session Order 
a. The selected cases will be randomly allocated into four (4) sets of 75 cases each, 
case subsets A, B, C, and D. Allocation will be balanced with respect to 
reference standard (cancer, benign, recall, and normal), and to the extent 
possible in the case sample, on presence of calcifications, breast composition 
(fatty or dense), and image acquisition site. 
b. Each study reader will be randomly assigned to a unique reading order. 
c. Each session has 300 cases that will be read: 150 FFDM cases and 150 DBT 
plus S-View cases for the two read visits.    
 
Table 5: One Possible Experimental Design 
 
 
Session 1 
 
Session 2 
 
Pat. 
Part 1 
Part 2 
 
Part 1 
Part 2 
Reader 
 
Gr. 1 
Gr. 2 
Gr. 1 
Gr. 2 
 
Gr. 1 
Gr. 2 
Gr. 1 
Gr. 2 
 
1 
B 
FFDM 
D  
DBT +  
C  
DBT +  
A 
FFDM 
W 
A  
DBT +  
C 
FFDM 
D 
FFDM 
B  
DBT +  
11, 17 
2 
A 
FFDM 
C  
DBT +  
D  
DBT +  
B 
FFDM 
A 
B  
DBT +  
D 
FFDM 
C 
FFDM 
A  
DBT +  
10, 20 
3 
C 
FFDM 
B  
DBT +  
A  
DBT +  
D 
FFDM 
S 
D  
DBT +  
A 
FFDM 
B 
FFDM 
C  
DBT +  
14, 21, 
24 
4 
D 
FFDM 
A  
DBT +  
B  
DBT +  
C 
FFDM 
H 
C  
DBT +  
B 
FFDM 
A 
FFDM 
D  
DBT +  
9, 19 
5 
B 
DBT +  
D 
FFDM 
C 
FFDM 
A  
DBT +  
O 
A 
FFDM 
C  
DBT +  
D  
DBT +  
B 
FFDM 
8, 15 
6 
A  
DBT +  
C 
FFDM 
D 
FFDM 
B  
DBT +  
U 
B 
FFDM 
D  
DBT +  
C  
DBT +  
A 
FFDM 
7, 16 
7 
C  
DBT +  
B 
FFDM 
A 
FFDM 
D  
DBT +  
T 
D 
FFDM 
A  
DBT +  
B  
DBT +  
C 
FFDM 
12, 18 
8 
D  
DBT +  
A 
FFDM 
B 
FFDM 
C  
DBT +  
 
C 
FFDM 
B  
DBT +  
A  
DBT +  
D 
FFDM 
13, 22, 
23 
Pat. = Pattern. Gr. = Group. Reader numbers begin with 7 to prevent confusion with reader 
numbers on the pilot study. DBT + = DBT plus S-View. 
 
 
Interpretation Results: For each case, the readers are asked to provide two sets of results 
from two reading visits separated by a memory washout period. 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 complementary FFDM and DBT plus S-View during the second 
visit.  
 
 

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11. The Lesion Matching Process 
11.1 
Purpose 
The purpose of the lesion matching process will be to determine if the location and type of a 
finding identified by the reader matches those of a malignant lesion annotated by the truther, 
i.e., correct lesion localization and type.  
11.2 
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 pivotal 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 II 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. 
11.3 
Conduct of the Lesion Matching Process 
11.3.1 Core Matching Center 
Lesion matching will take place remotely, with results documented within the truther/lesion 
matching database. 
11.3.2 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 Subject 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.  
 
11.3.3 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 Subject ID number. The lesion matcher compares the finding location(s) and 
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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 corresponding Reader Sequence ID number to 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 reader’s eCRF that contains the 
corresponding Subject ID number and Reader Sequence 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 1: 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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12. 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, that is, 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, because slice numbers apply only to DBT plus S-View. 
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, for example, 
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. 
12.1 
Analysis Set 
Intent-to-Diagnose Population The intent-to-diagnose population comprises each reader’s 
interpretation of each study case in each modality (FFDM, DBT plus S-View). Missing 
interpretations are not anticipated. We plan to include all readers’ interpretations of all cases in 
both modalities in the analysis set. If any protocol deviations or violations occur, the statistician 
will evaluate them to determine their impact on the integrity of the study database; and will 
determine whether any affected data points should be excluded from primary analysis. 
 
12.2 
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. 
12.3 
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 12.3.1 and 12.3.2, 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. 
 
 

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12.3.1 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-subject sensitivity and specificity based on BI-
RADS categories. 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. 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 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 overall POM score 
recorded by the reader for the case, and the overall BI-RADS category 
recorded by the reader for the case will be used, after describing those 
findings. 
 
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 

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that modality will be assigned to the case and the BI-RADS score 
for this case will be assigned as category 1. 
 
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 6: Per-subject POM and BI-RADS scores  
(requiring correct lesion localization) 
 
Reference standard 
Reader’s interpretation 
Per-subject POM and BI-RADS Scores 
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 BI-RADS category recorded 
by the reader for the case 
One or more findings located 
in this case 
POM: Overall POM score recorded by the 
reader for the case 
BI-RADS: Overall BI-RADS category recorded 
by the reader for the case 
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 BI-RADS 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 matching findings 
BI-RADS: Highest BI-RADS category recorded 
by the reader for any of those matching findings 
 
 
12.3.2 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 7: 
 
If a case has no proven malignancies: 
 
If the reader does not initially recall the case; or if the reader initially recalls 
the case and then records overall recall decision no: The recall score for this 
case will be the same as the recall score recorded by the reader for the case, 
that is, no recall.  
 
If the reader initially recalls the case and records overall recall decision yes: 
The recall score for this case will be the same as the recall score recorded by 
the reader for the case, that is, recall. 

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 
If a case has one or more proven malignancies: 
 
If the reader initially recalls the case, records one or more findings that are 
determined by the truther to match the location(s) of any proven malignancies 
in this case, and records overall recall decision yes: The recall score for this 
case will be the same as the recall score recorded by the reader for the case, 
that is, recall. 
 
If the reader does not initially recall the case; or if the reader initially recalls 
the case and then records overall recall decision no; or when the reader 
initially recalls the case and records overall recall decision yes, 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, that is, 
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 7:  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 (initially or overall) 
Same as recall recorded by the reader 
for the case, that is, no recall 
Recall (initially and overall) 
Same as recall recorded by the reader 
for the case, that is, recall 
One or more malignancies 
 
No recall (initially or overall) 
Same as recall recorded by the reader 
for the case, that is, no recall 
Recall (initially and overall); 
Findings in this case, but no 
findings matching the location(s) 
of any proven malignancies in 
this case 
Assigned as no recall 
Recall (initially and overall); 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, that is, recall 
 
12.3.3 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 
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 
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. 
 
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. 
12.4 
Subgroups 
Analysis of per-subject and per-lesion sensitivity is limited to the subgroup of subjects with 
cancer. Sensitivity will be analyzed in subjects with cancer overall, and may be analyzed in 
further subgroups defined by lesion types (for example, masses, calcifications). Recall rate also 
will be analyzed in the subgroup of subjects with cancer. 
Analysis of per-subject specificity is limited to the subgroups of subjects without cancer. Recall 
rate also will be analyzed in the subgroups of subjects without cancer, and may be analyzed in 
the subset of recall cases. If analysis is performed in the subset of recall cases, complementary 
analysis will be performed in the subset of normal cases and in the subset of benign cases. 
Performance metrics (AUC, sensitivity, specificity, and/or recall rate) also may be analyzed in 
the subgroup of women with dense breasts (BI-RADS breast composition categories c. The 
breasts are heterogeneously dense, which may obscure small masses and d. The breasts are 
extremely dense, which lowers the sensitivity of mammography). If analysis is performed in the 
subset of women with dense breasts, complementary analysis will be performed in the subset of 
women with non-dense breasts. 
12.5 
Analysis of Primary Endpoint 
The primary endpoint on this study is per-subject AUC requiring correct lesion localization. 
Primary analysis will not involve pooling across study radiologists, to allow for heterogeneity 
among them. We will estimate AUCs for each reader in each review condition (FFDM, DBT plus 
S-View) based on per-subject POM scores as described in section 12.3. 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 will be assigned to the breast. 
We will provide graphs of each reader’s ROC curve for each review condition, and an 
average empirical ROC plot within each review condition. For each reader the non-
parametric (trapezoidal) AUC for the FFDM read, the DBT plus S-View read, and the 

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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 study will be considered to have successfully demonstrated safety and effectiveness of 
the Fujifilm ASPIRE Cristalle DBT plus S-View system if the per-subject average AUC for 
DBT plus S-View is statistically significantly non-inferior to the average AUC for FFDM at the 
alpha = 0.05 significance level, for non-inferiority margin delta = 0.05. This will be 
established if the lower limit of the two-sided 95% CI for the difference in average AUC for 
DBT plus S-View – FFDM lies entirely above –0.05. 
 
12.6 
Analysis of Secondary Endpoints 
When analyzing secondary aims per-subject POM, BI-RADS, and recall scores requiring 
correct lesion localization will be derived as described in 12.3.1 and 12.3.2. Two-sided 95% 
CIs will be used to quantify uncertainty. 
 
1. 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).11 
2. 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 also will use the MRMC 
method of Obuchowski and Rockette (1995).11 
3. 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 recall rates for all 
cancer cases. 
4. Superior per-subject average AUC for DBT plus S-View versus FFDM, based on 
POM scores and requiring correct lesion localization 
Analysis will be performed similarly to analysis of the Primary Aim. Superiority will be 
established if the lower limit of the two-sided 95% CI for the difference in average 
AUC for DBT plus S-View – FFDM lies entirely above zero (0). 
5. Non-inferior and/or 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 be performed similarly to analysis of per-subject 
sensitivity. 

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6. Superior (lower) per-subject average recall rate for DBT plus S-View versus FFDM 
for all recall cases (follow-up proven non-cancer cases) 
Analysis of per-subject recall rate for all recall cases will be performed similarly to 
analysis of per-subject recall rates for all non-cancer cases. If analysis is performed 
in the subset of recall cases, complementary analysis will be performed in the subset 
of normal cases and in the subset of benign cases. 
7. Non-inferior per-lesion average sensitivity for masses, masses with calcifications, 
focal asymmetries, and/or architectural distortions for DBT plus S-View versus 
FFDM, based on BI-RADS scores requiring correct lesion localization, using non-
inferiority margin delta = 0.10 
We plan to use methods for clustered data from MRMC studies that take into 
account the correlation between lesions in the same case when analyzing 
lesion-level sensitivity. In particular, Rao and Scott’s (1992)14 method for estimating 
proportions from clustered data will be used to obtain estimates for each reader in 
each reading condition, and Obuchowski’s (1998)12 extension of this to a pair of 
correlated proportions will be used to estimate the variance-covariance matrix of all 
possible pairs of proportions. The usual Obuchowski and Rockette (1995)11 MRMC 
method will then be applied to perform inferences that generalize to the population of 
readers and the population of cases while also taking into account within-case 
correlations between lesions. 
8. Non-inferior and/or superior per-lesion average sensitivity for calcifications and/or 
masses with calcifications 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-lesion sensitivity for calcifications and/or masses with calcifications 
will be performed similarly to analysis of per-lesion sensitivity for masses, masses 
with calcifications, focal asymmetries, and/or architectural distortions. 
9. Non-inferior (margin delta = 0.05 for AUC, 0.10 for other performance metrics) and/or 
superior average AUC and/or other performance metric(s) for DBT plus S-View 
versus FFDM for subjects with dense breasts (BI-RADS breast composition 
categories c. The breasts are heterogeneously dense, which may obscure small 
masses and d. The breasts are extremely dense, which lowers the sensitivity of 
mammography). 
Analysis will performed similarly to corresponding analysis above. If analysis is 
performed in the subset of women with dense breasts, complementary analysis will 
be performed in the subset of women with non-dense breasts. 
 
 
Multiple Comparisons. We will use a graphical approach to illustrate relationships among 
endpoints and protect the study’s type 1 error rate from inflation.13,17 The testing strategy is 
shown in a figure with vertices (nodes) for each hypothesis to be tested and directed paths 
(arrows) between vertices. All study hypotheses to be formally tested as potential marketing 
claims are shown in the graph. Hypotheses are denoted H1, H2, …, Hk, …, Hm, where m is 
the total number of hypotheses to be tested. Each hypothesis to be tested is allocated initial 
endpoint-specific alpha, k, and the sum 1 + 2 + … + k + … + m =  for the study overall, 
0.05. Initial endpoint-specific alpha can be 0 for endpoints of lesser importance; hypotheses 
for these endpoints will receive alpha from hypotheses that are rejected and direct alpha 
toward them.  

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Each directed path is assigned a weight between 0 and 1 indicating how much of the 
endpoint-specific alpha moves along the path when a hypothesis is rejected. The sum of 
weights leaving any hypothesis equal to 1, that is, all of the preserved alpha is used in 
receiving hypotheses. Paths may include a loop-back feature whereby if only one of a pair of 
looping hypotheses is rejected at its endpoint-specific k, that k loops back to the other 
hypothesis to increase its endpoint-specific alpha. Testing in a strategy with loop-back can 
start with any vertex that has initial endpoint-specific k > 0, and all such vertices can be 
tested until one is found for which the null hypothesis is rejected; then testing follows the 
arrows. Finally, conditional passing of alpha is shown by paths with negligible weights 
epsilon (); this places higher priority on other hypotheses until those have been tested. 
 
The graph is continually updated each time a null hypothesis is successfully rejected, as 
follows: 
1. Pass k from successful Hk according to the path weights. 
2. Eliminate the vertex for Hk. 
3. Connect all incoming arrows to outgoing arrow tails of the deleted vertex. 
4. Adjust path weights based on relative weights of previous parts of path. Maintain: 
a) Sum of endpoint-specific k =  and b) Sum of outgoing weights from each vertex = 1. 
5. If a new path duplicates an existing path, combine them and add their weights. 
 
 
On this study we are interested in testing the following hypotheses:  
 
             Table 8:  Hypotheses to be tested                                                                           
Hypothesis Endpoint 
Null 
Hypothesis 
Alternative 
Hypothesis 
Non-inferiority 
margin, delta 
H1 
AUC 
Inferior 
Non-inferior 
0.05 
H2 
Per-subject recall rate for all 
non-cancer cases 
Inferior 
Non-inferior 
0.05 
H3 
Per-subject recall rate for all 
cancer cases 
Inferior 
Non-inferior 
0.10 
H4 
Per-subject sensitivity 
Inferior 
Non-inferior 
0.10 
H5 
Per-subject recall rate for all 
non-cancer cases 
Equal 
Superior  
N/A 
H6 
Per-subject specificity 
Inferior 
Non-inferior 
0.05 
H7 
AUC 
Equal 
Superior  
N/A 
H8 
Per-subject sensitivity 
Equal 
Superior  
N/A 
 
 
H1 corresponds to the study’s primary endpoint. Testing will use the full study alpha: 
1 =  = 0.05. Hypothesis testing for secondary endpoints will only proceed if H1 is 
rejected, in which situation 1 will be passed to one or more of H2, H3, and/or H4 through 
path weights w12, w13, and w14, respectively. These weights will sum to 1, and one or two 
of them may be 0. 
 
H2, H3, and H4 correspond to higher priority secondary endpoints. Their initial endpoint-
specific alphas are zero, because they are only tested if the study’s primary aim is met. If 

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that occurs their endpoint-specific alphas are updated to k = w1k × 1. Each of H2, H3, 
and H4 may pass alpha to either of the others, and this may involve loop-back. One or 
more of H2, H3, and/or H4 also may pass alpha to one or more of H5 through H8, and this 
may be conditional on first testing all of H2, H3, and H4. 
 
H5 through H8 correspond to secondary endpoints with lower priority and/or likelihood of 
success. Their initial endpoint-specific alphas are zero. Each of these may receive alpha 
from H2, H3, and/or H4. Each of H5 through H8 may pass alpha to the others, and this 
may involve loop-back. 
 
All path weights will be provided in a separate, pre-specified analysis plan, with weights 
finalized prior to analyzing any study reading data. Paths with weight 0 will not appear in 
the final graphic. 
 
 
 
 
Figure A. One example of a graphical method to control study type I error rate. 
 
 
12.7 
Sample Size Calculations 
A sample size of at least 60 cancer cases, 240 non-cancer cases, and 18 readers was 
selected for this study. Sample sizes were calculated to show non-inferior AUC on a per-
subject basis (primary endpoint).  
We used the method of Obuchowski (1995, 2000)12,19 to determine the number of readers 
required in a fully crossed design to provide 80% power at statistical significance level alpha 
= 0.05 for the multi-reader, multi-case (MRMC) F*-test when the number of positive cases 
(cancers) is 60 and the number of non-cancer cases is 240. Calculations were made based 
on the following assumptions: 
 
Endpoint: Difference in average area under ROC curve (A) for  DBT plus S-View 
versus FFDM 
 
Significance level alpha () = 0.05 
H1 
H2 
H3 
H5 
H4 
H6 
 = 0.05 
 
 
 
 
 

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 
Target power = 0.80 
 
Non-inferiority margin delta () = 0.05 
 
Average area under ROC curve (A) for FFDM, A1 = 0.80 
 
Under the null hypothesis of inferiority, the average area under the ROC curve for 
DBT plus S-View is A2 = 0.75 
 
For calculating power under the alternative hypothesis of non-inferiority, A2 = A1 
 
Correlation of A within reader, between reading conditions; r1= 0.53 
 
Difference in correlation of A between reader, within reading condition versus 
between conditions; r2 – r3= 0.02 
 
Correlation between the set of A from each reading condition, rb= 0.73 
 
Variance of A in population of readers, within reading condition, 2
b = 0.0016 
 
Variance of A when the same reader interprets the same case sample in the same 
reading condition, 2
w = 0.0001 
 
Variance of A because cases are a sample, 2
c, calculated using a binormal 
approximation (Obuchowski, 1994)15. This variance depends on the value of A and 
on the numbers of cancer and non-cancer cases in the sample. 
Estimates of power for MRMC studies are highly dependent on the assumptions above. We 
therefore also obtained the number of readers required to provide 80% protected power 
allowing for possible attrition or parameter misspecification: 
 
15% attrition rate for either cases or readers. 
 
Decrease in the comparator metric, A1, to 90% of its assumed value. 
 
If power decreased when a parameter value increased, we increased said parameter 
by 50% on the measurement scale or by 125% on the variance scale. 
 
If power decreased when a parameter value decreased, we decreased said 
parameter by 33% on the measurement scale. 
Table 8 shows that a study with 18 readers, 60 cancers, and 240 non-cancers, provides at 
least 80% protected power. 
 

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Table 9: Estimated Power for Primary Endpoint: Non-inferior AUC 
 
Power (%)* 
Initial values**: A1 = 0.80, , n = 
60 cancers + 240 non-cancers,
2
ab =0.0004 from 2
b = 0.0016 and rb= 
0.73, r1 = 0.53, (r2 – r3) = 0.02 and 2
w = 
0.0001 
92 
0.90A1 
91 
0.85n 
89 
0.85R 
88 
2.252ab 
85 
0.67r1 
88 
2.252
w 
91 
1.5(r2 - r3) 
89 
*Power calculated using Student’s t distribution with R – 1 degrees of freedom 
and rounded down to nearest whole percent. 
** A1 = Area under the ROC curve with FFDM.  = Non-inferiority margin. 
2
ab = variance for interaction between reader and reading condition, obtained 
as the product of between-reader variance 2
b and 1 minus the correlation 
between the set of AUCs in the two reading conditions, rb. r1correlation of 
AUCs within reader, between reading conditions.r2 – r3 = difference in 
correlation of AUCs between reader, within reading condition versus between 
conditions. 2
w = within-reader variance. Variance because cases are a sample, 
2
c, calculated using a binormal approximation (Obuchowski, 1994)15 
 
 
13 
Sponsor and Investigational Site Requirements (Study Administration) 
13.1 
Ethics 
13.1.1 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.  
 
13.1.2 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. 
 
13.2 
Reader Informed Consent 
Each reader must provide written informed consent before participating in the reader study 
of this protocol. 
 
13.3 
Protocol Compliance 
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
reader, the protocol shall be conducted as described. Any such change must be reported 
immediately to Fujifilm or its representative(s) and the governing IRB. 
13.3.1 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 study reader, 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 readers enrolled in the study and must also be used to re-consent 
readers already enrolled in the study, if they are affected by the amendment. 
 
13.4 
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, and unless otherwise requested by the sponsor, for a period of 2 years after 
the later of the following two dates  as per 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. 
 
13.5 
Data Collection and Management 
13.5.1 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.  
13.5.2 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. 
13.5.3 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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13.6 
Confidentiality 
13.6.1 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. 
13.6.2 Reader Confidentiality 
Information collected during the pivotal reader study will be reported in such a way as to 
preclude identification of any individual radiologist’s performance. A unique blinded ID 
number will be assigned to each radiologist participating in the pivotal reader study for 
entry on the eCRFs. A master list of these ID numbers for the radiologists participating in 
the pivotal reader study will be securely maintained by the Fujifilm project manager. 
13.6.3 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).  
 
 
 
13.7 
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). 
13.8 
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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13.9 
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. 
13.10 
Financial Disclosure 
 
In accordance with 21CFR54, the principal investigator and the study readers will provide 
Fujifilm or its designee sufficient and accurate information on financial interests (proprietary or 
equity interests and payments exclusive of clinical study costs) to allow complete disclosure 
documenting lack of conflict of interest. The principal investigator, the pivotal 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. 
13.11 
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 Fuji, 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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14 
References 
1. American Cancer Society. Cancer Facts & Figures.  Available at:  
https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-
facts-figures-2018.html. Accessed February 28, 2018. 
 
2. American Cancer Society. Breast Cancer Risk and Prevention. Available at: 
https://www.cancer.org/cancer/breast-cancer/risk-and-prevention.html  Accessed 
February 28, 2018.  
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. Sickles EA, Wolverton DE, Dee KE. Performance parameters for screening and 
diagnostic mammography: specialist and general radiologists. Radiology. 2002; 
224:861-869. 
7. Sickles EA, Miglioretti DL, Ballard-Barbash R, et al. Performance benchmarks for 
diagnostic mammography. Radiology. 2005; 235:775-790. 
8. National Cancer Institute. Breast Cancer Surveillance Consortium data. Available at: 
http://breastscreening.cancer.gov/data/variables/. Accessed July 14, 2017. 
9. Warner, E.  Breast-Cancer Screening. The New England Journal of Medicine. 
2011,365:1025-1032. 
10. Conant E, Wan F, Thomas M, et al. Implementing Digital Breast Tomosynthesis (DBT) in 
a Screening Population: PPV1 as a Measure of Outcome. Presented at RSNA 2013, 
SSK01-02 Breast Imaging (Digital Breast Tomosynthesis Screening Outcomes) 
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. Obuchowski NA, on the comparison of correlated proportions for clustered 
data.Statistics in Medicine.1998 17(13): 1495–1507. 
13. Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009 Feb 15;28(4):586-604. 
14. Rao JNK, Scott AJ. A simple method for the analysis of clustered binary data, Biometrics 
1992; 48:577–585. 
15. Obuchowski NA. Computing sample size for receiver operating characteristic studies. 
Invest Radiol 1994; 29:238–243. 
16. SenoClaire DBT Option to Senographe Essential FFDM System – Summary of Safety 

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and Effectiveness Data (SSED) for P130020 (August 26, 2014). 
17. U.S. Department of Health and Human Services Food and Drug Administration 
CDER/CBER. Multiple Endpoints in Clinical Trials – Guidance for Industry. January 
2017.  
18. Selenia Dimensions 3D System – Summary of Safety and Effectiveness Data (SSED) 
for P080003 (September 24, 2010) and P080003/S001 (October 24, 2012).  
19. 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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15 
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 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 (P160031) 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 B. ASPIRE Cristalle - 
Fujifilm’s Mammography acquisition 
system 
Figure C. ASPIRE Bellus II - 
Fujifilm’s Mammography Viewer 
Acquisition of FFDM and DBT plus S-View Images by ASPIRE Cristalle (Figure B) 
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 C) 
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 S-View images. 
The viewer supports typical image-manipulation functions, such as windowing-and-leveling, 
zooming, etc. 
Viewer 
Console 
PC 
Exposure Unit 
Acquisition 
Workstation 

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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 four-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)