Comparison of the Philips MicroDose Tomosynthesis System to 2D Digital Mammography
Phase: NA
Conditions: Breast Cancer
Sponsor: Philips Digital Mammography Sweden AB

 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
 
 
Security Classification: 
For internal use 
Author:  
Britta Stenson/Users/Mamea 
Document ID and Revision: 
DOC-MTIN-9RWH8K-8.0 
Approved by:  
 
SPONSOR 
 
Sponsor’s Legal Entity:  
Philips Digital Mammography Sweden AB 
Box 1111 
SE-171 22 Solna 
Sweden 
Business Unit:  
Mammography Solutions 
Department:  
Product Marketing 
NCT number: 
NCT02615509 
 
 
APPROVAL PRINCIPAL INVESTIGATOR 
I, Etta Pisano, M.D., Principal Investigator of this clinical investigation, approve the clinical 
investigational plan described in Document ID DOC-MTIN-9RWH8K dated 2015 August 12. 
 
Name 
Function 
Date 
Signature 
Etta Pisano, M.D. 
Principal investigator 
 
 
 
 
 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 2 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
REVISION HISTORY 
Date 
Rev. 
Author 
Changes/Comments 
2015 Jan 15 
1.0 
Miriam von Tiedemann 
First PMA supplement version (based 
on DOC-VHAT-9JMGAX) 
20015 July 3 
2.0 
Elin Moa/Sonia Souza 
Updated protocol according to feedback 
from clinical investigators; 
Updated schematic flow chart of 
enrollment (fig 2) 
 
2015 July 15 
3.0 
Sonia Souza/Elin Moa 
Updated objectives and statistical 
section 
2015 Aug 12 
4.0 
Jonas Rehn 
Updated Study Design to ensure 
balanced enrollment from the different 
sources 
2015 Aug 12 
5.0 
Jonas Rehn 
Minor editorial change 
2016 
6.0 
Jonas Rehn  
No changes to protocol content 
Version signed by Dr Pisano added.  
Protocol content still equivalent to 
version 5.0. 
2015 December 
12 
7.0 
Britta Stenson 
No changes to protocol content 
Document re-approved by clinical 
evaluator, project manager and 
regulatory affairs officer. 
Protocol content still equivalent to 
version 5.0. 
2016 April 13 
8.0 
Britta Stenson 
No changes to protocol content 
Clarified revision history   
Protocol content still equivalent to 
version 5.0. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 3 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
TABLE OF CONTENTS 
 
SPONSOR ................................................................................................................................................ 1 
APPROVAL PRINCIPAL INVESTIGATOR .............................................................................................. 1 
REVISION HISTORY ............................................................................................................................... 2 
TABLE OF CONTENTS ........................................................................................................................... 3 
SUMMARY ............................................................................................................................................... 6 
1. 
STATEMENT OF COMPLIANCE ..................................................................................................... 7 
2. 
ABBREVIATIONS USED .................................................................................................................. 8 
3. 
INTRODUCTION AND RATIONALE ................................................................................................ 9 
3.1. Rationale ....................................................................................................................................... 9 
3.2. Literature review ........................................................................................................................... 9 
3.3. Device description ........................................................................................................................ 9 
3.3.1. 
Intended use of the investigational device during the investigation / Indications for Use 
statement. ...................................................................................................................................... 10 
3.3.2. 
Populations and indications for which the device is intended, including contraindications
 
10 
3.3.3. 
Device description ......................................................................................................... 10 
3.3.4. 
Pre-clinical testing .......................................................................................................... 11 
3.3.5. 
Device risk analysis and risk assessment ..................................................................... 12 
3.3.6. 
Conclusion ..................................................................................................................... 12 
4. 
OBJECTIVES AND HYPOTHESES ...............................................................................................13 
4.1. Primary Objective .......................................................................................................................13 
4.2. Secondary Objectives .................................................................................................................13 
4.3. Supplementary Objectives ..........................................................................................................13 
5. 
STUDY DESIGN .............................................................................................................................14 
5.1. General .......................................................................................................................................14 
5.2. Comparators ...............................................................................................................................15 
5.2.1. 
Maintenance and calibration .......................................................................................... 15 
5.3. Subjects ......................................................................................................................................15 
5.3.1. 
Inclusion criteria ............................................................................................................. 15 
5.3.2. 
Exclusion criteria ............................................................................................................ 16 
5.3.3. 
Enrollment and duration ................................................................................................ 16 
5.3.4. 
Number of Subjects and Readers ................................................................................. 16 
5.3.5. 
Procedure for the replacement of subjects .................................................................... 16 
5.3.6. 
Subject withdrawal or discontinuation ........................................................................... 16 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 4 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
5.4. Procedures .................................................................................................................................16 
5.4.1. 
Image Accrual ................................................................................................................ 16 
5.4.2. 
Image Reading .............................................................................................................. 17 
5.4.3. 
Case selection - Image Reading ................................................................................... 18 
5.4.4. 
Reader Selection ........................................................................................................... 19 
5.4.5. 
Reader Training ............................................................................................................. 19 
5.4.6. 
Case Selection ............................................................................................................... 20 
5.5. Endpoints ....................................................................................................................................22 
5.5.1. 
Clinical Endpoint: Image Accrual Phase........................................................................ 22 
5.5.2. 
Clinical Endpoint: Image Reading Phase ...................................................................... 22 
5.5.3. 
Procedure Endpoint ....................................................................................................... 23 
5.5.4. 
Safety Endpoint ............................................................................................................. 23 
5.6. Monitoring Plan ...........................................................................................................................23 
5.7. Deviations from the clinical plan .................................................................................................24 
6. 
STATISTICAL CONSIDERATIONS ...............................................................................................24 
6.1. Sample Size and Number of Readers Justification ....................................................................24 
6.1.1. 
Sample Size Justification for Primary Efficacy Analysis ................................................ 24 
6.1.2. 
Sample Size Justification for Average Glandular Dose ................................................. 26 
6.1.3. 
Sample Size Justification for Recall Rate ...................................................................... 26 
6.1.4. 
Sample Size Justification for Sensitivity Non-inferiority Analysis .................................. 26 
6.1.5. 
Sample Size Justification for Specificity Non-inferiority Analysis .................................. 27 
6.2. General Statistical Considerations .............................................................................................28 
6.3. Subject Disposition .....................................................................................................................28 
6.4. Demographics and Baseline Characteristics ..............................................................................28 
6.5. Readers Compliance ..................................................................................................................28 
6.6. Primary Efficacy Analysis ...........................................................................................................28 
6.7. Effect of Missing Values on Primary Efficacy Analysis...............................................................29 
6.8. Secondary Efficacy Analysis ......................................................................................................29 
6.9. Supplementary Efficacy Analysis ...............................................................................................31 
7. 
DATA MANAGEMENT ...................................................................................................................31 
7.1. Access to Source Documents ....................................................................................................31 
7.2. Retention period .........................................................................................................................32 
7.3. Data Management ......................................................................................................................32 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 5 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
8. 
DEVICE ACCOUNTABILITY ..........................................................................................................32 
9. 
INFORMED CONSENT PROCESS ...............................................................................................32 
10. ADVERSE EVENT REPORTING ...................................................................................................33 
10.1. Complaint ....................................................................................................................................33 
10.2. Reporting ....................................................................................................................................34 
10.3. Anticipated and unavoidable adverse device effects .................................................................34 
11. EARLY TERMINATION OR SUSPENSION OF THE RESEARCH ...............................................34 
12. PUBLICATION POLICY .................................................................................................................35 
13. REFERENCES ...............................................................................................................................35 
APPENDIX I: LIST OF INVESTIGATORS AND SITES .........................................................................37 
APPENDIX II: LIST OF MONITOR(S)/CLINICAL SCIENTIST ...............................................................38 
 
 
 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 6 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
 
SUMMARY 
Study Title (ID) 
Comparison of the Philips MicroDose Tomosynthesis to 2D Digital Mammography  
Subjects 
Approximately 800 women who fulfill all inclusion and exclusion criteria will be enrolled 
in chronological order from up to 3 different US sites with one study investigator for 
each site.  Two cohorts of patients will be enrolled (i.e., Biopsy and Screening 
Cohorts). Paired sets of a standard 4-view exam will be collected both from Philips 
Tomosynthesis system (Tomosynthesis and synthetic 2D images) and a FDA-cleared 
FFDM system. All enrolled cases will be quality controlled for completeness of image 
and patient information.  Inclusion criteria: 
 
Female and at least 40 years of age 
 
No contraindication for routine bilateral mammography 
Screening Cohort 
 
Patient presents for a routine screening mammogram 
Biopsy Cohort 
 
Patient is scheduled for a biopsy  
 
Patient has a screening detected abnormality  
The reading portion of the study will include approximately 300 normal cases (including 
some cases determined to be normal after call back after screening mammography), 
65 cancer cases, and 40 biopsy proven benign cases. 
The primary objective of the study is to compare the safety and clinical performance of 
the Philips MicroDose Tomosynthesis system (Tomosynthesis and synthetic 2D) 
images to conventional 2D mammography images (FFDM).  
Study Design 
The study will be performed in two phases:  Image Accrual and Image Reading. Image 
accrual will be performed in a multicenter setting. Image reading will be designed as a 
multi-case, multi-reader (MCMR) study with paired image acquisition and reader 
evaluation. Approximately 18 American Board of Radiology (ABR) certified, and 
Mammography Quality Safety Act (MQSA) qualified radiologists will review and score 
the cases.  
 
Outcome of the reader study for the two imaging groups will be compared using ROC 
methodology. 
Treatment Groups  
 
Investigational Device: Philips MicroDose Tomosynthesis system (Tomosynthesis 
prototype Philips MicroDose SI S0) 
 
Comparator: Digital mammography system (2D FFDM) 
Primary Objectives 
The primary objective of the study is to compare the safety and clinical performance of 
the Philips MicroDose Tomosynthesis system (tomosynthesis and synthetic 2D) 
images and 2D digital mammography (from any FDA cleared FFDM system) images. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 7 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
Clinical performance will be based on the Area under the Receiver Operating 
Characteristics curve (ROC AUC). The ROC curves will be generated using a 
confidence scores (CS) using a numeric scale. The ROC curves will be calculated for 
each reader. 
 
Secondary 
Objectives 
The secondary objectives are: 
 
To compare the average glandular dose for exams performed with Philips 
MicroDose Tomosynthesis system and the 2D mammography system (2D 
FFDM. 
 
To compare the non-cancer recall rate for Philips MicroDose Tomosynthesis 
system and 2D mammography exams.  
 
To compare the sensitivity and specificity of the Philips MicroDose 
Tomosynthesis system (tomosynthesis and synthetic 2D) to that obtained with 
a 2D mammography system (2D FFDM). 
The average glandular dose (AGD) will be recorded per subject for each breast 
(right and left) and view (CC and MLO). Sensitivity will be estimated for each 
reader as the proportion of cancer cases with per-case BI-RADS category 4 or 
higher.  Specificity will also be estimated by reader as the proportion of non-cancer 
cases with per-case BI-RADS category less than 4. Cancer determination will be 
based on biopsy results or the outcome of the one-year follow-up exam. 
 
Supplementary 
Objectives 
The following supplementary objectives will be evaluated: 
 
 
The effect of breast density on AUC for images obtained using the Philips 
MicroDose Tomosynthesis system and 2D mammography system (2D FFDM). 
Breast density will be stratified as fatty (i.e., BI-RADS breast density type A and B) 
and dense (BI-RADS breast density type C and D). 
 
To compare the average image interpretation time for exams performed with 
Philips MicroDose Tomosynthesis and 2D mammography system (2D FFDM). 
1. 
STATEMENT OF COMPLIANCE 
This clinical research shall be conducted in accordance with the Clinical Investigation Plan, and with 
the ethical principles that have their origin in the Declaration of Helsinki and all applicable regional 
and/or national regulations. Furthermore, all investigators will complete financial disclosures, as 
outlined in the 21 CFR part 54. Investigators located in the US shall follow the 21 CFR parts 50, 56 
and 812.  
This clinical research shall not be started prior to obtaining a favorable opinion from an Ethics 
Committee (EC)/Institutional Review Board (IRB) and Regulatory authority/Food and Drug 
Administration (FDA), if required. Any additional requirements imposed by the EC/IRB and/or 
regulatory authority/FDA shall be followed. Insurance shall be provided for the subjects participating in 
this clinical trial according to local law. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 8 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
2. 
ABBREVIATIONS USED 
 
Abbreviations 
Explanation of abbreviation 
ABR 
American Board of Radiology 
ACR 
American College of Radiology 
AGD 
Average Glandular Dose measured in [mGy] 
AUC 
Area Under the Curve 
BI-RADS 
Breast Imaging‐ Reporting and Data System 
CC 
Craniocaudal 
CI  
Confidence Interval 
CRF 
Case Report Form 
CRA  
Clinical Research Associate  
CS 
Confidence Score 
DBT  
Digital Breast Tomosynthesis 
DF 
Degree of Freedom 
EC 
Ethics Committee 
EUREF 
European Reference Organisation for Quality Assured Breast 
Screening and Diagnostic Services 
FDA 
Food and Drug Administration 
FFDM 
Full Field Digital Mammography (all U.S. marketed FFDM units 
incl. MicroDose SI L50) 
FOM 
Figure-of-Merit 
FROC 
Free Receiver Operating Characteristics 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
MLO 
Medio-lateral oblique 
MQSA 
Mammography Quality Standards Act 
MRMC  
Multi-Reader, Multi-Case 
NI 
Non-inferiority 
Synthetic 2D 
A projection image calculated from tomosynthesis data. Does 
not require additional radiation exposure. 
2D, FFDM 
Conventional digital mammography 
DBT plus synthetic 2D 
 
Only tomosynthesis images are acquired, and a synthetic 2D 
image is calculated. Both images are read together. 
ROC 
Receiver Operating Characteristics 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 9 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
3. 
INTRODUCTION AND RATIONALE 
3.1. 
Rationale 
Breast cancer is one of the most common cancer types among women around the world. 
Approximately one in eight American women will be diagnosed with breast cancer in her life time [1]. 
Early detection of cancer leads to a better prognosis with a bigger chance to survive the disease. As 
such, screening programs have been developed to identify non-palpable breast cancer in 
asymptomatic women with x-ray imaging.  While there have been numerous technologies used for 
breast cancer screening, the gold standard since the late 1970s has been x-ray based mammography 
[2]. 
Population based mammography screening has in some studies been shown to reduce breast cancer 
mortality by between 40% and 45% [3]. Digital mammography has supplanted film-screen 
mammography during the last ten years and diagnostic performance of the newer technology has now 
been proven in several large studies [4]-[6]. Digital mammography enables efficiency improvements 
and opportunities of future advanced applications such as spectral imaging, tomosynthesis and phase 
contrast imaging.  
Tomosynthesis provides a three-dimensional reconstruction of the breast which is of interest both for 
screening and diagnostic procedures. The image reconstruction enables cross-sectional visualization 
of the breast tissue reducing difficulties of interpretation of projection images of overlapping tissue or 
superposition.  
3.2. 
Literature review  
Tomosynthesis is intensively marketed by the major mammography vendors, notably Hologic, GE and 
Siemens. A growing body of clinical data supports increased cancer detection rates, and also in some 
locations, reduced non-cancer recall rates [7]. The technology has passed the early adopter phase 
and is now moving into the mass market. Recently it was reported that 30% of the radiologists in the 
US used tomosynthesis in their practice and that 62% of the remaining radiologists report that they 
planned to obtain it soon [8].  
In spite of the trend towards fast adoption of tomosynthesis there are still many major markets where 
the transition from 2D mammography to tomosynthesis is still expected to take many years. Guidelines 
for quality control as well as standards for safety and essential performance are still works in progress 
for tomosynthesis. Furthermore screening guidelines and reimbursement systems do not yet support 
tomosynthesis in screening.  
3.3. 
Device description 
The investigational device, Philips MicroDose SI version S0, Tomosynthesis prototype system 
(referred to as Philips MicroDose Tomosynthesis here) is developed by Philips Digital Mammography 
Sweden AB, a Philips Healthcare company. The proposed Philips MicroDose Tomosynthesis system 
is a based on the same technology as the FDA cleared FFDM device, Philips MicroDose SI. 
The investigational device includes MicroDose SI S0 Tomosynthesis system with software version 
11.0. 
The manufacturer of the investigational device is: 
Philips Digital Mammography Sweden AB 
Box 1111 
SE-171 22 
Sweden 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 10 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
3.3.1. 
Intended use of the investigational device during the investigation / Indications 
for Use statement. 
The intended medical purpose of the Philips MicroDose Tomosynthesis is to produce radiographic 
images of the human breast for the purpose of diagnostic and screening mammography. The Philips 
MicroDose Tomosynthesis system is intended to be used in the same clinical applications as 2D 
mammography systems. 
 
The intended medical purpose of the investigational device is to collect clinical data to support the 
PMA submission for Digital Breast Tomosynthesis (DBT) device. The examination where the 
investigational device will be used is a standard 4-view mammogram, i.e., medio-lateral oblique (MLO) 
and craniocaudal (CC) views of each breast, performed on asymptomatic women to detect the 
presence of breast cancer. Repeat standard views might be done for technical reasons, such as 
inadequate compression, inadequate amount of included breast tissue, or over- or underexposure. 
3.3.2. 
Populations and indications for which the device is intended, including 
contraindications  
The digital tomosynthesis mammography system is intended to support examinations of the human 
breast of both women and men. 
Women invited for screening are usually in the age of 40 to 70, depending on the local regulations. 
Patients coming for diagnostic examinations are of any adult age. 
3.3.3. 
Device description  
The design of the MicroDose Tomosynthesis system is based on the currently marketed MicroDose SI 
L50, which was cleared by FDA via K123995 – February 1, 2013. Due to the close similarity of the two 
devices, most design features that are described in the 510(k) are applicable to the MicroDose 
Tomosynthesis system as well.   

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 11 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
 
Figure 1. Overview of the MicroDose Tomosynthesis system. 
Like the currently marketed MicroDose SI L50, the MicroDose tomosynthesis system consists of an 
acquisition workstation, a main cabinet and a side cabinet. With the exception of the side cabinet, 
these components are shown in Figure 1. In fact, these parts are the same in both systems. The main 
difference between the MicroDose Tomosynthesis system and the currently marketed MicroDose SI 
Model L50 is the design of the C-arm. 
3.3.4. 
Pre-clinical testing 
The product development project of the MicroDose Tomosynthesis system will be managed according 
to applicable parts of the Philips Digital Mammography’s Product Development Process. The design 
will be verified according to the design verification processes on the first MicroDose Tomosynthesis 
system. The subsequent systems will be produced by limited production processes. To ensure that the 
subsequent systems will comply with the verified design, a predefined amount of test, selected via 
impact analysis, will be performed on each system. All risk related requirements will be verified on all 
systems. 
The pre-clinical testing will put specific focus on image and radiation quality. The image quality tests 
include (but are not limited to) tests of exposure time, image areas, detector linearity, scatter rejection, 
spatial resolution, contrast-to-noise and signal-to-noise ratios, tests of the automatic exposure control, 
image homogeneity, contrast-detail resolution, and the Mammographic Accreditation Phantom. The 
radiation quality tests include (but are not limited to) tests of the tube output and generator accuracy, 
dose, half value layer, x-ray field, leakage radiation and protective shielding . 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 12 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
Regular quality control (QC) will be performed on the system according to a protocol aligned with the 
most recent version of the EUREF quality control procedures. 
Change control will be performed according to applicable development processes. Issues found during 
verification and validation will be registered in a project issue database handled by a cross functional 
team (change control board). In addition to the internal testing described above, compliance 
verification will be conducted both in-house and by third party test house Intertek. 
3.3.5. 
Device risk analysis and risk assessment  
The risk management procedure is followed for the project. After performing risk analysis of the Philips 
MicroDose Tomosynthesis system, there are certain identified residual risks with justification. These 
risks are mainly related to software, x-ray exposure, moving parts during image acquisition, electronics 
of the photon-counting detector and high voltage used for X-ray. 
A significant part of the identified justified risks are related to software. The technology of producing 
high quality digital images from a photon-counting imaging system can only be solved with software, 
for example image processing algorithms, image acquisition, data storage and data transfer, which are 
critical functions to the system performance. We still consider the risks of the system to be as-low-as–
reasonably-practicable. 
The scanning collimator is a necessary function when using multi-slit beam geometry to receive a 
tomosynthetic motion. This geometry reduces the dose to the examined patients. In summary, the 
benefit of Philips MicroDose overweighs the related risks. 
3.3.6. 
Conclusion 
The benefit of the study is to enable new technology that potentially could increase early detection and 
reduce breast cancer mortality. Furthermore the technology is also expected to reduce radiation dose 
level compared to existing commercially available flat panel systems. 
As the subjects enrolled in the study will be imaged both with tomosynthesis and conventional 2D 
mammography, additional lesions could be detected in the screening patients that would not have 
been found only with conventional 2D mammography. However a direct benefit of the enrolled 
subjects is not expected. Possibly a missed cancer on the 2D mammogram could be detected on the 
tomosynthesis image. Another scenario is that a benign lesion is detected which could require 
additional imaging or even biopsy. The tomosynthesis images alone will not be used to make a 
decision to biopsy, but further work-up of such lesions with conventional imaging might indicate the 
need for biopsy. If a lesion is found on the tomosynthesis images but not detected on 2D, the 
radiologist at site might want to do additional imaging to assess the lesion. For the majority of the 
enrolled patients in the study, there will be no direct benefit as of participating in the study, though it is 
possible that a cancer that is missed on the 2D might be detected. 
A risk that the enrolled subjects in the study are taking when participating in the study, is that they will 
be exposed to additional radiation.  The radiation of the investigations device is comparable to Philips 
MicroDose SI, which is a low dose digital mammography system (approx. 0.8 mGy per view for a 
standard examination).   
 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 13 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
4. 
OBJECTIVES AND HYPOTHESES  
4.1. 
Primary Objective 
The primary objective of the study is to compare the safety and clinical performance of the Philips 
MicroDose Tomosynthesis system (Tomosynthesis and synthetic 2D) images to conventional 2D 
mammography images (FFDM). 
Clinical performance will be based on the Area under the Receiver Operating Characteristics (ROC) 
Curve. The ROC curves will be generated using the confidence scores (CS) based on a numeric 
scale. ROC curves will be calculated for each reader. 
The following hypothesis will be evaluated: 
Null Hypothesis: Ho:  ϴ2 - ϴ1 ≥ ∆ 
Alternative Hypothesis:  ϴ2 - ϴ1 < ∆ 
Where ϴ1 (Philips) and ϴ2 (FFDM) are the area under the Receiver Operating Characteristic (ROC) 
curve (AUC) for radiologists interpreting mammograms obtained on the Philips MicroDose 
Tomosynthesis system or FFDM, respectively. Delta (∆) is the chosen non-inferior margin of 0.05. 
4.2. 
Secondary Objectives 
The secondary objectives are: 
 
To compare the average glandular dose for exams acquired on Philips MicroDose Tomosynthesis 
system and the 2D mammography system. 
 
To compare the non-cancer recall rate for Philips MicroDose Tomosynthesis system and 2D 
mammography exams. 
 
To compare the sensitivity and specificity of the Philips MicroDose tomosynthesis system (i.e., 
Tomosynthesis and synthetic 2D) to that obtained with 2D mammography. 
The average glandular dose (AGD) will be recorded per subject for each breast (right and left) and 
view (CC and MLO).  The following hypothesis will be evaluated: 
 
Null Hypothesis: Ho:  µ2 - µ1 > δ 
 
Alternative Hypothesis:  µ2 - µ1 ≤ δ 
where µ1 and µ 2 are the mean average glandular dose (i.e., radiation dose) for the Philips MicroDose 
Tomosynthesis system and FFDM system, respectively, and δ is 10% of the FFDM radiation dose. 
The non-cancer recall rate will be recorded per subject.  The following hypothesis will be evaluated: 
 
Null Hypothesis: Ho:  π2 - π 1 = 0 
 
Alternative Hypothesis:  π 2 - π 1 ≠ 0 
where π1 and π 2 are the non-cancer recall rate for the Philips MicroDose Tomosynthesis system and 
FFDM system, respectively. 
Sensitivity will be estimated for each reader as the proportion of cancer cases with per-case BI-RADS 
category 4 or higher. Specificity will also be estimated by reader as the proportion of non-cancer cases 
with per-case BI-RADS category less than 4. Ground truth will be based on biopsy results or the 
outcome for the woman after one year follow-up.  
4.3. 
Supplementary Objectives 
The following supplementary objectives will be evaluated: 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 14 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
 
To evaluate the effect of breast density on AUC for images obtained using the Philips MicroDose 
Tomosynthesis system and 2D mammography system. Breast density will be stratified as fatty 
(i.e., BI-RADS breast density type A and B) and dense (BI-RADS breast density type C and D). 
 
To compare the average image interpretation time for exams performed with Philips MicroDose 
Tomosynthesis system and 2D mammography. 
 
To assess the diagnostic performance of the Philips MicroDose Tomosynthesis compared to the 
FFDM  
5. 
STUDY DESIGN   
5.1. 
General 
The study is a multicenter, multi-case, multi-reader (MCMR) study with paired image acquisition and 
reader evaluation. The study will be performed in two phases: Imaging Accrual phase and Imaging 
Reading phase. 
Approximately 800 women who fulfill all inclusion and exclusion criteria will be enrolled in 
chronological order from approximately 3 different US sites with one study investigator for each site. 
Two cohorts of patients will be enrolled (i.e., Biopsy and Screening Cohorts). Paired sets of a standard 
4-view synthetic 2D and tomosynthesis slices exposed on Philips MicroDose Tomosynthesis system 
and 4-view mammograms on a FDA cleared FFDM system will be collected. All enrolled cases will be 
quality controlled for completeness of image and patient information. 
A subset of the images collected as part of this study will also be used to validate the spectral breast 
density measurement. This validation is specified in a separate study protocol [9]. 
Depending on the experience at the sites, each site could also enroll up to 10 additional women to 
train the technologists on using the system and whose images will be used for training purposes. 
These cases will not be used in the reader study. In addition to these cases, images for reader training 
will be available that have been previously collected under another IRB approved protocol.  
Approval for the study will be obtained from the ethics committees for all participating centers. All 
eligible subjects will provide written informed consent prior to entry into the study, which is defined as 
being imaged on the Philips MicroDose Tomosynthesis system and an FFDM system. Subject 
enrollment will be monitored by the sponsor at each site. All subjects will be consecutively enrolled. 
All subjects interested in participating in the study will be assigned a unique study identification 
number. At the time of providing informed consent, subjects will be assigned the next number in 
sequence from the list of study identification numbers. After study enrollment, subjects will be 
identified solely by their study identification number on the Case Report Forms (CRF). In addition, all 
subject specific information will be removed from the images prior to them being electronically 
submitted to the study sponsor and only the subject’s study identification number will be provided. 
Each participating site will maintain a database linking the study number to subject identification. 
To protect against any bias during the imaging acquisition, the order in which the subject is imaged on 
either the investigational device or the FFDM will be randomized, except for patients that have 
undergone a screening exam including 2D. In this case, the patient will be imaged only with the Philips 
MicroDose Tomosynthesis system (since the 2D mammogram has been acquired previously). 
Reimaging will only be performed if more than 45 days have passed since the original acquisition. A 
randomization list will be generated for each cohort (i.e., the biopsy and screening cohort).  
The mode of the eligibility screening exam (source) will be recorded. To protect from case selection 
bias, not more than 60% of the cases in the reader study can originally be screened with 2D or 
tomosynthesis. In this aspect combo screening (2D + tomosynthesis) is regarded as tomosynthesis. 
The enrollment and randomization flow for each cohort is presented in Figure 2. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 15 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
 
 
Figure 2: Patient Enrollment and Randomization by Cohort 
5.2. 
Comparators 
As of today mammography screening with 2D mammography is the global standard of care. 
Tomosynthesis is only recently approved for screening and is not reimbursed in many countries, and 
has no harmonized quality control procedure.  
Also there are no established guidelines for Tomosynthesis in terms of angles, dose, number of slices 
required or how it should be used. Therefore this study uses 2D mammography as the comparator. 
5.2.1. 
Maintenance and calibration  
The system will be maintained and calibrated according to the systems manual.  
5.3. 
Subjects 
Subjects participating in the study will be selected based on the inclusion and exclusion criteria: 
5.3.1. 
Inclusion criteria 
 
Patient is female and at least 40 years of age 
 
No contraindication for routine bilateral mammography 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 16 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
Screening Cohort 
- 
Patient presents for a routine screening mammogram 
Biopsy Cohort 
- 
Patient is scheduled for a biopsy  
- 
Patient has a screening detected abnormality  
5.3.2. 
Exclusion criteria 
 
Patient is pregnant or believes she may be pregnant; OR, 
 
Patient is breast feeding; OR 
 
Patient is unable or unwilling to give informed consent, including consent to reuse data for future 
research; OR, 
 
Patient has breast implants; OR  
 
Patient has previous surgical biopsy; OR 
 
Patient has previous breast cancer; OR 
 
Patient presented to screening with clinical symptoms (e.g. palpable lump, nipple discharge, 
nipple retraction, skin irritation or dimpling) 
5.3.3. 
Enrollment and duration 
Subjects are considered to be enrolled in the study after they have signed the informed consent form. 
No study procedures will be performed before this moment.  
The study period, per subject, is approximately up to 90 minutes and is limited to a single 
mammography session, except for the normal cases which will require a one-year follow-up exam 
(normal screening exam, not using the investigational device).  
5.3.4. 
Number of Subjects and Readers  
Approximately 800 patients who fulfill all inclusion and exclusion criteria and pass the quality control 
for completeness of image and patient information will be enrolled in the image accrual phase of the 
study.   Among these patients approximately 300 normal, 65 cancer, and 40 biopsy-proven benign 
cases will be included in the image reading phase of the study.  
The numbers of readers, and the overall sample size justification for the study is detailed in the 
Statistical considerations, section 6 of this protocol. 
5.3.5. 
Procedure for the replacement of subjects 
Subjects will not be replaced. 
5.3.6. 
Subject withdrawal or discontinuation 
Subjects can withdraw informed consent at any time during the trial. 
5.4. 
Procedures  
5.4.1. 
Image Accrual 
The subjects will be recruited to either the biopsy cohort or the screening cohort as discussed in 
section 5.1. If the inclusion/exclusion criteria are met for either cohort, the subject will be asked to 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 17 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
participate in the study. The enrollment procedure will include study brief, inclusion/exclusion criteria, 
informed consent, randomization and data base entry (using a CRF). If the subject has no prior 2D 
screening exam, she will be randomized to either be imaged first on the investigational device and 
thereafter on the FFDM system, or the other way around. Imaging will be acquired by a trained 
technologist at site. Data management will be performed by a study assistant from each site; this 
includes anonymization, export, updated CRF etc. 
5.4.2. 
Image Reading 
The readers will independently review Philips MicroDose Tomosynthesis images and FFDM screening 
mammograms in two separate sessions using dedicated softcopy review workstations. The reading 
sessions will be separated by a wash-out period of at least one month. There will be equal numbers of 
cancer cases and equal mixture of FFDM and Tomosynthesis exams in each group. 
Each reader will work at a designated workstation and will complete the case report forms 
independently. Readers will read in private reading rooms with very low ambient lighting. A study 
assistant will be available in the lab but not in the reading room to monitor each reader’s progress and 
to resolve any issues that are unrelated to the actual image interpretation.  
The review of Tomosynthesis will include reading of the Tomosynthesis (CC and MLO) plus 
synthetized 2D images (CC and MLO) generated from the tomosynthesis images. The review of 
FFDM exams will include reading the standard bilateral 2-view mammograms (CC and MLO). No 
patient history or other clinical information will be provided to the readers. Each reader will have a 
case lists displaying images in the prescribed order for each reader session.  
The reader will review the images for a given modality then will follow the reporting workflow 
depending upon whether they would recall the patient or not based on the imaging data presented. 
The Confidence Scores for recalled cases will have to fall between (51 and 100) and the confidence 
scores for the no recall cases will have to fall somewhere between (1 and 50). For the per-case ROC 
analysis, the confidence score for the case will be the overall score documented by the reader.   
5.4.2.1. No Suspicious Findings (No Recall) Reporting 
If the reader believes that a case contains no suspicious lesion(s), the reader will be asked to assign 
an overall forced BI-RADS® rating and a confidence score of the case being normal (1 to 50). The 
score 1 represents the least suspicious No-Recall case, whereas the score 50 represents the least 
suspicious No-Recall case. The allowed forced BI-RADS ratings are 1 and 2 for all cases that the 
radiologist interprets as containing NO suspicious, including benign lesion(s) that he or she is not 
recommending for additional imaging after screening. 
5.4.2.2. Suspicious Findings (Recall) Reporting 
For each of the image sets, the reader will examine the images and look for any area of concern. For 
each suspicious lesion(s) triggering the need to recall a patient, the reader will localize the lesion(s) by 
providing the laterality and an o’clock location, assign a forced BI-RADS® rating, and  the confidence 
score of the lesion being malignant (CS) (51 to 100) will be reported. The score 51 represents the 
least suspicious recall case, whereas the score 100 represents the most suspicious recall case. The 
reader will also provide the lesion type and size. After marking and rating all lesions, the reader will be 
asked to assign an overall BI-RADS® rating and CS score for the whole case. The allowed forced BI-
RADS® ratings for suspicious lesion(s) are 3, 4, or 5. BI-RADS® 0 rating is not allowed in this study.  
The annotations of suspicious lesion(s) will be made on the softcopy review workstation using the 
software features of case review application.  

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 18 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
5.4.2.3. Matching Reader Indicated Lesion Locations to Truth 
For all cancer cases, the lesion location(s) provided by the readers will be assessed for 
correspondence to the known cancer locations. For purposes of analysis, the cases which the reader 
assigns a score of BI-RADS 3 or higher and which correspond to the known cancer location (as 
described below) will be considered as correctly localized.  
5.4.2.4. Correct Localization: 
A reader will get credit for correct localization of a cancerous lesion if the laterality matches the true 
laterality of the cancer and any of the three rules below apply: 
 
Reader recorded lesion at a specific o’clock location anywhere from 1 to 12 is the same as the 
o’clock location documented by the truther within 2 o’clock ticks. 
 
Lesions indicated by the truther as being located in the Subareolar region that is reported as 
Subareolar by the reader. 
 
Lesions indicated by the truther as in the Axillary Tail region must be reported in either the Axillary 
Tail or 10, 11, or 12 o’clock (right breast) or 12, 1, 2 (left breast) by the reader.  
5.4.3. 
Case selection - Image Reading 
Cases for the reader study will be selected from all of the cases acquired through the case acquisition 
phase. A total of approximately 65 cancers, 40 cases with benign biopsies and 300 normal cases will 
be selected in sequential order to fulfill the requirements for case stratification.  The 300 normal cases 
will include some cases that were recalled from screening but ultimately determined to be normal after 
additional work-up, as well as cases that were not recalled from screening. Approximately 10% 
additional cases will be included to protect from loss to follow-up prior to 1 year status verification.  
Case stratification is described in detail in 5.4.6. In summary, cancer cases will be stratified by lesion 
type and size, and breast density.  Benign cases will be stratified by lesion type and breast density. 
Normal cases will be stratified by breast density and by the recommendation for additional work-up 
after screening. Once the target case number is reached data collection will stop.   
Approximately 18 American Board of Radiology (ABR) certified and Mammography Quality Safety Act 
(MQSA) qualified radiologists will review and score the cases according to Image Review methods 
described Image Reading, Section 5.4.2. All readers will undergo training on interpretation using the 
Philips MicroDose tomosynthesis system images to become familiar with the images and the review 
workstation to be used in the study. 
To avoid recall bias, the reading will be divided in two sessions structured using a crossover design 
with a washout period of one month between sessions as presented in Figure 3. 
 
   Session1  
 
                                                 Session 2  
 
 
 
 
 
 
 
 
Figure 3: Reading Scheme 
Group A 
 Modality 1  
First half of cases 
1 Month Washout 
Group B 
 Modality 2  
Second half of cases  
Group A 
 Modality 2 
First half of cases 
Group B 
 Modality 1  
Second half of cases  

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 19 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
Each reader will independently review 2D mammograms and MicroDose images (i.e., Tomosynthesis 
and synthetic 2D) of the same patient in separate sessions to minimize memory effects. The cases will 
be randomly divided into two groups, Group A and Group B. In the first reading session, the readers 
will read Group A with modality 1 and Group B with modality 2. In the second reading session, the 
readers will read Group A with modality 2 and Group B with modality 1. Within each reading session, 
the order in which the cases will be read will be randomized to avoid confounding the device effect 
with reading order effects.    
Each reading session may be divided into several visit times to adapt to the readers' schedule. 
Furthermore, to avoid bias, no patient history or other clinical information will be provided to the 
reader. 
5.4.4. 
Reader Selection 
The readers will be a mixture of general radiologists and breast imaging subspecialists to reflect the 
pool of potential users in clinical practice. All readers will be MQSA-qualified, ABR Board-certified 
radiologists. The readers’ experience level with reading tomosynthesis images will be documented.   
The following inclusion criteria must be met for readers: 
 
MQSA qualified radiologist  
 
ABR Board Certified 
 
At least 2 years in clinical practice including interpretation of digital mammograms 
 
All potential readers must complete the Philips tomosynthesis training and test session in order to 
be a valid reader in the actual study. 
The radiologists will provide the following documentation in support of determining their eligibility 
reader study coordinator and maintained in the reader’s study folder: 
 
Curriculum Vitae 
 
Medical License 
 
Qualification Survey which will record the name and address of their radiology practice, the years 
of experience in interpreting digital mammograms. 
Documentation of completion of Philips tomosynthesis training by each reader will be included in the 
reader’s study folder kept on site with a copy in the Philips study master file.  
5.4.5. 
Reader Training 
The goal of the reader training sessions is to assure that the readers are sufficiently trained in the 
interpretation of Philips tomosynthesis images. Training will be conducted by an expert radiologist with 
an application specialist experienced in the softcopy review workstation operation will be on hand to 
assist readers with use of the review workstation in order for the readers become familiar with its 
functionality.  
The training will consist of two parts, Part 1: an initial overview of tomosynthesis and synthetic 2D 
presented by radiologist training with subsequent discussion of a series of 20 training cases and Part 
2:  Independent review by the reader of 30 additional cases.   
5.4.5.1. Part 1 Training 
The training data set will consist of 10 biopsy-proven cancer cases (5 calcifications, 5 mass) and 10 
biopsy-proven benign lesions (5 calcifications, 5 mass) cases and 10 normal cases. During the initial 
review, the cases will be presented side by side for comparison of tomosynthesis and synthetic 2D 
and FFDM images. The trainer will point out the range of typical anatomy and abnormalities identified 
with tomosynthesis. Training will also include protocol procedure training on reading images from 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 20 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
tomosynthesis and FFDM systems, review station software tools, instructions for use of the 
Confidence Scales, instruction regarding completion of the Case Report Forms (CRFs) and a hands-
on session at the review workstation to provide the Readers with an overview of their functionality and 
standard image review tools for tomosynthesis and FFDM viewing. Reader trainees will also be given 
written instructions on image interpretation, which they may refer to during the training sessions. 
5.4.5.2. Part 2 Training 
After this initial training, all readers will required to independently review and score thirty 
tomosynthesis and synthetic 2D case sets. These sets will consist of 10 malignant cases, 10 benign 
cases, and 10 normal cases and complete the CRFs. Following the independent read of this case set, 
a study assistant will review the reader’s completion of all CRFs in training to make sure they 
understand the process. 
No cases used in training will be used in the reader study. 
5.4.6. 
Case Selection  
5.4.6.1. Selection of Normal Cases 
A normal – no recall case  is defined as a case classified as BIRADS 1 or 2 by initial screening clinical 
reporting from the sites with confirmation that no cancer has been diagnosed after 1 year of follow-up 
past enrollment to the study.  A normal – recall case is defined as a case classified as BIRADS 1 or 2 
after completion of the diagnostic workup following an abnormal screen triggering recall. 
A total of approximately 300 normal cases, 270 normal-no recall and 30 normal-recall will be 
sequentially selected by the statistician from all cleared cases which approximately represents the 
distribution of breast densities in the general population, including almost entirely fatty, scattered 
fibroglandular elements, heterogeneously dense and extremely dense breast as presented in Table 2.  
 
Stratification criteria 
Target 
Min (-30%) 
Breast density 
 
 
 
A: Almost entirely fat 
11% / 32 
22 
 
B: Scattered fibroglandular densities 
43% / 129 
90 
 
C: Heterogeneously dense 
39% / 117 
82 
 
D: Extremely dense 
7% / 22 
16 
Table 2:  Stratification Criteria for Normal Cases (n=300) in accordance with [6] 
5.4.6.2. Selection of Cases that are benign at biopsy 
In addition, cases that were benign at biopsy will be selected among those cases that had benign 
proven biopsy. A biopsy benign case is defined as a case for which the subject undergoes biopsy of 
one or more breast lesions that were all determined pathologically to be benign with confirmation of 
non-cancer status after 1 year of follow-up past enrollment of the study. 
27 benign cases (by imaging) will be sequentially selected by the statistician from all cleared cases 
which approximately represents the distribution of breast densities in the general population, including 
almost entirely fatty, scattered fibroglandular elements, heterogeneously dense and extremely dense 
breast. Both mass and calcifications findings type will be included. 
13 biopsy benign cases will be sequentially selected by the statistician from all cleared cases which 
approximately represents the distribution of breast densities in the general population, including almost 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 21 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
entirely fatty, scattered fibroglandular elements, heterogeneously dense and extremely dense breast. 
Both mass and calcifications findings type will be included. One year follow-up will be documented 
prior to the final statistical analysis. The stratification for benign cases is presented in Table 3. 
 
Stratification criteria 
Target 
Min (-30%) 
Lesion type 
 
 
 
Calcification 
43% / 17 
12 
 
Mass 
57% / 23 
16 
Breast density 
 
 
 
A: Almost entirely fat 
11% / 4 
3 
 
B: Scattered fibroglandular densities 
43% / 17 
12 
 
C: Heterogeneously dense 
39% / 16 
11 
 
D: Extremely dense 
7% / 3 
2 
Table 3: Stratification criteria Benign Cases (n=40) 
5.4.6.3. Selection of Cancer Cases 
The final classification of a cancer case for potential inclusion in the reader study will be performed by 
an expert radiologist. The expert radiologist will be provided with the Philips MicroDose tomosynthesis 
system images, digital mammograms, and relevant clinical data including confirmation of a positive 
biopsy for cancer. The expert radiologist will record the visibility and location of the lesion on the CRF. 
65 positive cases will be selected to represent an enriched sample similar to the distribution of cases 
in a screening population which might be seen in clinical practice in the U.S. regarding lesion type, 
breast density distribution, and lesion size as presented in Table 4. 
 
Stratification criteria 
Target 
Min (-30%) 
Lesion type 
 
 
 
Calcification 
37% / 24 
17 
 
Mass 
48% / 31 
22 
 
Architectural distortion or asymmetry 
15% / 10 
7 
Breast density 
 
 
 
A: Almost entirely fat 
11% / 7 
5 
 
B: Scattered fibroglandular densities 
43% / 28 
20 
 
C: Heterogeneously dense 
39% / 25 
18 
 
D: Extremely dense 
7% / 5 
3 
Lesion size 
 
 
 
Minimal cancer (≤ 10 mm or DCIS) 
52.7% / 34 
24 
Table 4: Stratification criteria CANCER CASES (n=65) 
 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 22 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
5.5. 
Endpoints  
5.5.1. 
Clinical Endpoint: Image Accrual Phase 
For all participating subjects, the following information, as applicable will be collected during the 
imaging acquisition and recorded on the case report form (CRF):  
 
Demographics: Date of informed consent, date of birth, race, ethnicity, and menopausal status 
 
Medical History 
 
Breast Imaging-Reporting and Data System (BI-RADS) score will be performed by the interpreting 
radiologists for both the Philips MicroDose tomosynthesis mammograms and the FFDM. The 
following ratings will be used: 
o 
0 – Incomplete, 
o 
1 – Negative,  
o 
2 – Benign finding(s),  
o 
3 – Probably Benign,  
o 
4 – Suspicious abnormality, 
 
4 a  - Low suspicion for malignancy 
 
4 b – Moderate suspicion for malignancy 
 
4 c – High suspicion for malignancy 
o 
5 – Highly suggestive of Malignancy 
 
Screening Population cases will be classified as No Recall if both Tomo and FFDM exams have 
final assessment of BIRADS 1 or 2. Screening population cases will be classified as Recall if 
either Tomo or FFDM exam is classified as BI-RADS 0, requiring additional diagnostic imaging 
workup.   
 
Screening population cases that were recalled, 0, for additional diagnostic work-up must have a 
final BIRADS assessment of 1, 2, 3, 4a, 4b, 4c, or 5. 
 
The study imaging standard exam (Tomo or FFDM) that is performed prior to biopsy in the biopsy 
cohort arm must be interpreted and assigned a final BIRADS assessment of 1, 2, 3, 4a, 4b, 4c, or 
5. Breast density score: The breast density score will be performed at the acquisition site by at 
least one radiologists using the standard of care FFDM images. Cases will be categorized using 
BI-RADS breast density scale as either non-dense (BI-RADS breast density type A or B) or dense 
(BI-RADS breast density type C or D). 
 
Whether the case is scheduled for a screening mammogram or a biopsy 
 
Lesion type: Lesion type will be defined at the acquisition site using BI-RADS scale and classified 
as mass, calcifications, asymmetry, or architectural distortion.  
 
Biopsy results  
 
Images from the screening examination for the screening cohort 
5.5.2. 
Clinical Endpoint: Image Reading Phase 
The Readers will independently review Philips MicroDose Tomosynthesis images and FFDM 
screening mammogram for each case in two separate reading sessions separated by a wash-out 
period of at least one month. The cases to be included in the reader study will be divided into two 
groups with an equal number of cancer cases and an equal number of FFDM and tomosynthesis 
exams in each group.  
The review of FFDM exams will include reading the standard bilateral 2-view mammograms (CC and 
MLO).  The review of Tomosynthesis will include reading of the Tomosynthesis (CC and MLO) plus 
synthetized 2D images (CC and MLO) generated from the tomosynthesis images.  No patient history 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 23 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
or other clinical information will be provided to the Readers. The following data points will be collected 
using case report forms which will be completed directly by the readers: 
 
Forced BI-RADS score of 1, 2, 3, 4a, 4b, 4c, or 5  
 
Confidence Score (CS): Readers will be asked to assign a confidence score for the BI-RADS 
ratings as follows: For BI-RADS 3 to 5, the confidence score represents the reader’s interpretation 
of the likelihood of the lesion being malignant on a scale of 51 to 100. The score 51 represents the 
least suspicious Recall case, whereas the score 100 represents the most suspicious Recall case. 
For BI-RADS 1 or 2, the confidence score represent the reader´s confidence that the case is 
normal and will range from 1 to 50. The score 1 represents the most normal No-Recall case, 
whereas the score 50 represents the least normal No-Recall case. For the per-case ROC analysis, 
the confidence score for the case will be the overall score documented by the reader.   
 
Readers will mark all lesions by location (breast and clock location).   
 
For the FROC analysis, each lesion or foci identified by the reader will rated using a confidence 
score that the abnormality in question representing a cancer “if it was actually present”. For this 
analysis confidence score will range from 1 to 100. A research associate (RA) located at the 
reader study facility will check the progress of the readers during each reading session. The RA 
will also check for missing data elements on the form and check all cases for completeness for 
each group of cases during the reading session. The RA will generate a query list to resolve any 
missing data points or cases prior to the reader ending a session. The RA will also assist readers 
with workstation problems and CRF issues should they arise.  
5.5.3. 
Procedure Endpoint 
 
Radiation dose: Average Glandular radiation dose will be read out from the DICOM header for 
each mammogram.  
 
Image interpretation time: Interpretation time will be measured during the reading study for each 
reader. The interpretation time includes the time the reader takes reviewing the case and 
completing the case report form. 
5.5.4. 
Safety Endpoint 
 
All expected or unexpected adverse events will be reported. 
5.6. 
Monitoring Plan 
Monitoring will be performed by a trained person appointed by Philips to ensure compliance with the 
Clinical Investigation plan, applicable national regulations and international standards, patient safety 
and data validity. The Sponsor may designate one or more individuals to monitor the progress of a 
clinical study. The Sponsor may also delegate the monitoring responsibilities to a third party. However, 
the Sponsor remains ultimately responsible for the conduct of the study. The Institution is responsible 
for the appropriate de-identification of subject data. The investigational site should provide access to 
the source data of the subjects. 
The monitor selected by the Sponsor will visit each site prior to study start and periodically during data 
collection phase. During each visit the monitor will review subject records including informed consent 
forms and case report form data. After each visit an on-site report will be written. A close-out visit for 
sites that have enrolled subjects will be conducted once the site has completed collecting data for the 
study. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 24 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
The monitor will ensure that all adverse device effects (anticipated and unanticipated) and complaints 
are reported to the sponsor in a timely manner and that unanticipated adverse device effects are 
reported to the IRB. 
A detailed plan for monitoring arrangement will be available separate from this protocol. 
Names of the monitor(s) can be found in Appendix II: List of monitor(s) of this protocol. An update of 
this list can be provided to the site under separate cover.  
5.7. 
Deviations from the clinical plan  
The Investigator is not allowed to deviate from the Clinical Investigation Plan or to enroll subjects that 
do not comply with all inclusion and exclusion criteria. Under emergency circumstances, deviations 
from the Clinical Investigation Plan to protect the rights, safety and well-being of human subjects may 
proceed without prior approval of the sponsor and the EC. Such deviations shall be documented and 
reported to the sponsor and the EC as soon as possible.  
All deviations from the Clinical Investigation Plan will be documented with date, subject, reason, 
actions taken and if the deviation affects subject's rights, safety and wellbeing or the scientific integrity 
of the clinical study. The deviation shall be notified to the Sponsor as soon as possible via the CRF. 
Deviations will be reviewed by the sponsor and in case of serious or repetitive deviations a corrective 
action plan may represent a need to initiate a corrective action plan with the principal investigator. In 
some cases, necessitate suspension of enrollment at the site or ultimately the principal investigator will 
be disqualified. 
6. 
STATISTICAL CONSIDERATIONS 
6.1. 
Sample Size and Number of Readers Justification 
6.1.1. 
Sample Size Justification for Primary Efficacy Analysis 
The primary endpoint is the Receiver Operator Characteristics curve analysis for both tests. In this 
trial, the 2D is the control test, and the tomosynthesis and synthetic 2D is the experiment test. The 
plan is to enroll approximate 800 patients, to include 65 patients with cancer, 40 biopsy-proven benign 
cases and 300 normal cases. The evaluations will be based on paired-cases and paired-readers that 
is all readers will interpret the test results of all patients in both tests (i.e., Philips MicroDose 
tomosynthesis system and FFDM).  
The sample size (number of readers) for the Reader Study is estimated based mixed-effects model for 
the diagnostic accuracy of a reader j using a particular diagnostic test i on reading occasion q as 
proposed by  Obuchowski [11]. The mixed model is specified as follows: 
  𝜃̂𝑖𝑗𝑞= 𝜇+ 𝜇𝑖+ 𝑟𝑗+ (𝑢𝑟)𝑖𝑗+ 𝜖𝑖𝑗𝑞          
Here, 𝑣𝑖=  𝜇+ 𝜇𝑖 is the mean accuracy of test i (fixed effect), rj is a random effect for reader j, (ur)ij is 
an interaction term for readers and tests (random effect), and 𝜖𝑖𝑗𝑞 is an error term. 
An F-statistic with 1 and (J-1) degree of freedom (df) will be used for testing the null hypothesis that 
the mean diagnostic accuracies of the tests are equal, where J is the number of readers. Under 
alternative hypothesis, the test statistic follows a non-central F distribution with 1 and (J-1) df, and the 
non-centrality parameter is estimated as following: 
𝜆̂ =
𝐽(𝜇1 − 𝜇2)2
2{𝜎̂𝑏
2(1 −𝜌̂𝑏) + 𝜎̂𝑤
2
𝑄+ 𝜎̂𝑐
2[(1 −𝜌̂1) + (𝐽−1)(𝜌̂2 −𝜌̂3)}
      

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 25 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
Thus, to calculate the statistical power, multiple parameters in the equation above need to be 
estimated. For this study, these estimates are based on the following assumptions: 
 
The type I error: α = 0.05 
 
AUC for control test: A = 0.85 
 
Number of positive patients: n1 = 65 
 
Number of negative patients: n2 = 300 
 
Non-inferiority margin: Δ = 0.05 
 
Variability between readers: 𝜎𝑏
2 = 0.0009 
 
Variability within the reader: 𝜎𝑤
2 = 0.000225 
 
Correlations: 𝜌1 = 0.46, 𝜌2 −𝜌3= 0 
 
Correlation: 𝜌𝑏 = 0.5 
 
Power for the non-inferiority test: 1 - β ≥ 0.8 
The variance between different patients 𝜎𝑐
2 will be calculated based on the method of Obuchowski 
(1994). It is suggested that for the ROC analysis, 𝜎𝑐
2 can be obtained as follows. 
𝜎𝑐
2 = 0.0099 × 𝑒−𝑎2
2 × [5𝑎2 + 8 + (𝑎2 + 8)/𝑅]
𝑛1
       
Where 𝑎= Φ−1(A) × 1.414 and Φ−1 is the inverse of the cumulative normal distribution function; n1 is 
the number of positive patients; and R is the ratio of the number of negative patients (n2) to positive 
patients (n1). 
The assumed AUC for control test (A) is 0.85. In a previous study on the Philips L30 system, the area 
under the ROC curve was 0.947, with a 95% C.I. (0.920, 0.974)[19]. In another similar study for the 
Hologic Tomosynthesis Mammography System, the AUC based on Probability of Malignancy for a 2D 
system is 0.867 [20]. Therefore for this study it is expected that the AUC for the control test will be 
approximately 0.85.  
The variance between readers interpreting the same patients 𝜎𝑏
2 is based on a study performed by 
Beam, Layde and Sullivan [16]; and it was widely used in previous studies. In a previous study on 
Philips L30 system [19], the estimated 𝜎𝑏
2 with 95% C.I. is 0.0005 (0.0003, 0.0013), thus a value of 
0.0009 is a reasonable estimation for 𝜎𝑏
2 in the proposed study. 
The variance within each reader interpreting the results of the same patients 𝜎𝑤
2 is estimated as one-
fourth of 𝜎𝑏
2, thus 0.00025. 
The four correlations are usually estimated from a pilot study or previous studies. Correlation for the 
same patients evaluated by the same reader using different tests (𝜌1), for the same patients evaluated 
by different readers with the same tests (𝜌2) and for the same patients evaluated by different readers 
and different tests (𝜌3) are based on suggestions from Obuchowski [11]. The correlation for the same 
reader to evaluate patients using different tests 𝜌𝑏 ranges from 0.44 to 0.86, based on Rockette et al. 
(1999). It is assumed that a correlation equal to 0.5 is a conservative estimate. 
Based on these values, 18 readers will be required to achieve statistical power of at least 0.80. 
 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 26 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
6.1.2. 
Sample Size Justification for Average Glandular Dose 
Another secondary objective of this study is to compare the average radiation dose between the 
Philips MicroDose tomosynthesis system and FFDM systems. Radiation dose will be evaluated based 
on the subject overall dose received during the examination. For the null hypothesis, no difference in 
radiation dose delivered to the patient during a mammographic exam between two systems, will be 
evaluated.  
Using historical data from the study site, the average radiation dose per breast for 20 subjects, 2 
sample (MLO + CC) was of 3.6 (standard deviation of 1.1), ranging from 2.4 to 6.7 for the GE FFDM, 
and of 2.6 (standard deviation of 0.7) ranging from 1.6 to 4.0 for Hologic mammography system. Also, 
in a previous study, comparing the three systems reported radiation dose per breast of 1.86, 2.91, and 
3.03, for Philips MicroDose, Hologic and GE, respectively representing a reduction of radiation of 
approximately 40% for MicroDose compared to Hologic and or the GE mammography system. 
Assuming that the standard deviation for the difference in radiation dose will be approximately 
1.5mGy, a sample size of approximately 100 subjects will allow for greater than 80% power to detect a 
difference in radiation between the two systems of approximately 0.5mGy (i.e., 10% of the overall 
patient radiation) using a paired t-test with a 0.025 one-sided significance level.   
6.1.3. 
Sample Size Justification for Recall Rate 
Based on the outcome of the most recent tomosynthesis PMA (i.e., MAMMOMAT Inspiration with 
Tomosynthesis, P140011), the recall rate for A FFDM alone was 0.438. For this study, a similar recall 
rate is expected.  Assuming that a 5% reduction in recall rate for tomosynthesis is clinically significant 
and adjusting for the multiple endpoints, a total of 2300 cases will allow for approximately 80% to 
detect an improvement in recall rate of approximately 5%.  Furthermore, assuming that the correlation 
among readers reading the same case in approximately 0.5, and that all subject will be read by all 18 
readers, approximately 250 subjects will be required. 
6.1.4. 
Sample Size Justification for Sensitivity Non-inferiority Analysis 
For the sensitivity analysis, the sample size estimation is based on the following assumptions: 
 
The type I error: α = 0.05  
 
 Sensitivity for control test: Se = 0.85 
 
 Number of positive patients: n1 = 65 
 
 Non-inferiority margin: Δ = 0.10 
 
 Variability between readers: σb
2 = 0.009 
 
 Variability within the reader: σw
2  = 0.00225 
 
 Correlations: ρ1 = 0.46, ρ2 −ρ3= 0 
 
 Correlation: ρb = 0.8 
 
 Power for the non-inferiority test: 1 - β ≥ 0.8 
The variance between different patients 𝜎𝑐
2 will be calculated based on a binomial approximation as 
follows: 
𝜎𝑐
2 = 𝑆𝑒(1 −𝑆𝑒)
𝑛1
         
Where Se is the expected sensitivity and n1 is the number of positive patients (i.e., patients with 
cancer). 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 27 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
In a previous study on the Philips MicroDose L30 system, the estimated sensitivity was 0.936, with a 
95% C.I. (0.897, 0.976) (see Statistics Collaborative, Inc., 2011). In another similar study for the 
Hologic Tomosynthesis Mammography System, the sensitivity for a 2D system was 0.862 Hologic, Inc. 
2012). Based on these previous results, it is expected that the sensitivity for both tests will be 
approximately 0.85. 
In a previous study on Philips MicroDose L30 [19] the estimated 𝜎𝑏
2 with 95% C.I. was 0.0035 (0.0019, 
0.0084). In another similar study for the Hologic Tomosynthesis Mammography System [20] the 
estimated 𝜎𝑏
2 with 95% C.I. was 0.0046 (0.0024, 0.0114). Thus a value of 0.009 is a reasonable 
estimation for 𝜎𝑏
2 in the proposed study. 
The variance within each reader interpreting the results of the same patients 𝜎𝑤
2 it is assumed to be 
one-fourth of 𝜎𝑏
2, thus 0.0025. 
Correlation for the same patients evaluated by the same reader using different tests (𝜌1), for the same 
patients evaluated by different readers with the same tests (𝜌2) and for the same patients evaluated by 
different readers and different tests (𝜌3) are based on suggestions from Obuchowski (2000). The 
correlation for the same reader to evaluate patients using different tests 𝜌𝑏 ranges from 0.44 to 0.86 in 
AUC analysis, according to Rockette et al. (1999 such correlation are usually higher for sensitivity 
analysis. Thus, it is expected that the value 𝜌𝑏 will be approximately 0.80 for this study. 
Based on these assumptions, for the sensitivity analysis, 18 readers will be required to achieve 
statistical power of at least 0.80, after adjusting for multiple endpoints. 
6.1.5. 
Sample Size Justification for Specificity Non-inferiority Analysis 
For specificity analysis, similar to sensitivity analysis, the following assumptions were made:  
 
The type I error: α = 0.05 
 
Specificity for control test: Sp = 0.70 
 
Number of positive patients: n2 = 300 
 
Non-inferiority margin: Δ = 0.10 
 
Variability between readers: 𝜎𝑏
2 = 0.012 
 
Variability within the reader: 𝜎𝑤
2 = 0.003 
 
Correlations: 𝜌1 = 0.46, 𝜌2 −𝜌3= 0 
 
Correlation: 𝜌𝑏 = 0.8 
 
Power for the non-inferiority test: 1 - β ≥ 0.8 
Similar to sensitivity analysis, the variance between different patients 𝜎𝑐
2 will be calculated based a 
binomial assumption, as described above. 
In a previous study on the Philips MicroDose L30, the estimated specificity was 0.764, with a 95% C.I. 
(0.688, 0.841) [19]. In another similar study for the Hologic Tomosynthesis Mammography System, the 
specificity for a 2D system was 0.651 [20]. Based on these previous results, it is assumed that the 
specificity for the control test is approximately 0.70.   
Also, in a previous study on Philips MicroDose L30 [19], the estimated 𝜎𝑏
2 with 95% C.I. was 0.0087 
(0.0047, 0.0208). In another similar study for the Hologic Tomosynthesis Mammography System [20], 
the estimated 𝜎𝑏
2 with 95% C.I. was 0.0144 (0.0077, 0.0357). Thus a value of 0.012 is a reasonable 
estimation for 𝜎𝑏
2 for the proposed study. 
The variance within each reader interpreting the results of the same patients 𝜎𝑤
2 is estimated as one-
fourth of 𝜎𝑏
2, thus 0.003. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 28 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
Correlation for the same patients evaluated by the same reader using different tests (𝜌1), for the same 
patients evaluated by different readers with the same tests (𝜌2) and for the same patients evaluated by 
different readers and different tests (𝜌3) are based on suggestions from Obuchowski [11]. The 
correlation for the same reader to evaluate patients using different tests 𝜌𝑏 ranges from 0.44 to 0.86 in 
AUC analysis, according to Rockette [18] such correlation are usually higher for sensitivity/specificity 
analysis. Thus, it is safe to assume the expected value 𝜌𝑏 to be 0.80 in the proposed study. 
Based on these assumptions, for the specificity analysis, 18 readers will be required to achieve 
statistical power of at least 0.80, after adjusting for multiple endpoints. 
6.2. 
General Statistical Considerations 
The primary analysis will be performed including all subjects selected for the reading portion of the 
study with confidence score for both Philips MicroDose tomosynthesis system and FFDM evaluation 
(modified intent to treat, MITT). For this analysis patient will be the basis for the analysis. Non-cancer 
cases, with missing one year follow-up will be assumed as cancer free case.  Missing values will be 
assumed to be missed at random.   
The analysis of safety includes all enrolled subjects in the acquisition portion of the study. 
Continuous variables will be summarized using the number of non-missing observations, mean, 
standard deviation, 95% Confidence Interval (CI) for the mean, median, minimum, and maximum; 
categorical variables will be summarized using the frequency count and the percentage of subjects in 
each category. Analyses will be conducted using SAS® software and OR-DBM MRMC software [12]. 
6.3. 
Subject Disposition 
Subject disposition, including total screened, enrolled in the acquisition and reading portion of the 
study, early terminations and withdrawals, will be presented. In addition, a listing will be provided with 
the reasons for discontinuation.  
6.4. 
Demographics and Baseline Characteristics 
Standard subject baseline characteristics (e.g., age, race and origin) will be summarized for all 
subjects enrolled in the imaging acquisition and imaging reading portion of the study. For continuous 
subject characteristics, means, standard deviation, median and range will be provided. The number of 
events and percentage of events will be presented for all categorical variables. 
6.5. 
Readers Compliance 
Reader compliance will be listed by image type. If applicable, comparability between the two image 
types (i.e., Philips MicroDose tomosynthesis system and FFDM) groups will be evaluated using a Chi-
square or Fisher’s exact test as appropriate. A listing of all deviations will be presented. 
6.6. 
Primary Efficacy Analysis 
The primary objective of the study is to compare the clinical performance of the Philips MicroDose 
tomosynthesis system (tomosynthesis with a synthetic 2D) images and 2D FFDM system. The primary 
endpoint is the Area under the ROC curve (AUC) using patient as the unit of analysis. The ROC 
curves will be generated using the confidence scores (1 to 100) and the reference standard (i.e., 
normal/benign or cancer).  All subjects with both Philips MicroDose tomosynthesis system and FFDM 
evaluation (modified intent to treat, MITT). For subjects with negative outcome for whom a 1 year 
follow-up is required, missing values will be removed from the study database.   
Smooth ROC curves and area under the curve will be estimated from the CS for each study reader 
interpreting images acquired with the Philips MicroDose tomosynthesis system and the FFDM 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 29 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
systems.  If smooth ROC curves cannot be fitted for each reader in each condition (e.g., if there is 
perfect performance), nonparametric methods may be used. Results will be summarized across 
readers using the method of [10] which includes random effects for study readers and uses the 
jackknife to handle correlation within cases, as obtained in the corresponding OR-DBM MRMC 
software. Robustness of the statistical method may be explored through use of the ANOVA model of 
Obuchowski and Rockette [11]; this model includes random effects for study readers, and adjusts 
variances and hypothesis tests for correlations due to having each reader interpret the same case 
sample. The degrees of freedom may be adjusted as suggested by Hillis [14].  The average AUC for 
Philips MicroDose tomosynthesis system and the FFDM, the average difference between the two 
systems, and its standard error for use in computing confidence interval and to performing hypothesis 
tests for the difference will be estimated.  
The following hypothesis will be evaluated: 
o 
Null Hypothesis: Ho:  ϴ2 - ϴ1 ≥ 0.05 
o 
Alternative Hypothesis:  ϴ2 - ϴ1 < 0.05 
Where ϴ1 is the average AUC for readers using the Philips MicroDose System (tomosynthesis + 
synthetic 2D) and ϴ2 is the average AUC for readers using the FFDM System.The Philips MicroDose 
tomosynthesis system will be considered non-inferior to the FFDM if the upper limit one-sided 95% CI 
for the difference in AUCs is less than 0.05.  AUC for Philips MicroDose tomosynthesis system and the 
FFDM will be also be presented by readers. 
6.7. 
Effect of Missing Values on Primary Efficacy Analysis  
To evaluate the effect of possible missing assessment for the reference standard (e.g., subjects does 
not return for one 1 year follow-up exam) sensitivity analysis will be performed to with missing values 
assigned as negative outcome, n – 1 assumed to be negative and 1 positive in random order,  or 
excluded from analysis.   
6.8. 
Secondary Efficacy Analysis 
The secondary objectives are: 
 
To compare the average glandular dose for exams acquired on Philips MicroDose 
Tomosynthesis system and the 2D mammography system. 
 
To compare the non-cancer recall rate for Philips MicroDose Tomosynthesis system and 2D 
mammography exams. 
 
To compare the sensitivity and specificity of the Philips MicroDose tomosynthesis system (i.e., 
Tomosynthesis and synthetic 2D) to that obtained with 2D mammography. 
Secondary objectives will only be tested if the null hypothesis for the primary endpoint is rejected. Four 
secondary endpoints will be evaluated. To control the Type I error, the following pre-specified order 
using a gatekeeper procedure as described by Dmitrienko et al. (2007) will be used: 
 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 30 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
Family 
Endpoint 
Procedure 
F1 
AUC ROC 
Test at the 0.05 level, no adjustment to the p-value 
F2 
Radiation Dose 
Test only if Ho for AUC ROC is rejected, p-value adjusted using 
HOLM procedure 
 
Recall Rate 
Test only if Ho for AUC ROC is rejected, p-value adjusted using 
HOLM procedure 
F2 
Sensitivity 
Test only if any Ho for F2 is rejected, p-value adjusted using HOLM 
procedure 
Specificity 
Test only if any Ho F2 is rejected, p-value adjusted using HOLM 
procedure 
 
The average glandular dose (i.e., radiation dose) refers to the total radiation dose during the exam and 
is expressed in mGy. The goal is to compare total radiation dose between the Philips MicroDose 
tomosynthesis system and the FFDM systems.  The following hypothesis will be tested: 
The average glandular dose (AGD) will be recorded per subject for each breast (right and left) and 
view (CC and MLO).  The following hypothesis will be evaluated: 
 
Null Hypothesis: Ho:  µ2 - µ1 > δ 
 
Alternative Hypothesis:  µ2 - µ1 ≤ δ 
where µ1 and µ 2 are the mean average glandular dose (i.e., radiation dose) for the Philips MicroDose 
Tomosynthesis system and FFDM system, respectively, and δ is 10% of the FFDM radiation dose.  
Analysis will be performed using an appropriate analysis of variance.  If the required assumptions for 
the ANOVA are violated, transformation of the data or non-parametric procedures may be used.  The 
95% confidence interval for the mean difference in radiation dose between the two systems will be 
constructed.  Under this Under this proposal Philips tomosynthesis will be declared as emitting less 
radiation then the FFDM if the upper bound of the 95% confidence interval for the difference in 
radiation dose is less than 10% of the FFDM. 
The non-cancer recall rate will be recorded per subject.  All negative screening, recalled and benign 
biopsy cases will be included. The following hypothesis will be evaluated: 
 
Null Hypothesis: Ho:  π2 - π 1 = 0 
 
Alternative Hypothesis:  π 2 - π 1 ≠ 0 
where π1 and π 2 are the non-cancer recall rate for the Philips MicroDose Tomosynthesis system and 
FFDM system, respectively.  
Recall rate will be analyzed using the concept of clustered binary data as described by Zhou et al 
(2011). In this case, each Reader will be considered as multiple observations within the same subject 
(cluster).  The 95% confidence interval for the difference in recall rate will be constructed.  If the upper 
limit to the one-sided 95% Confidence Interval for the difference (Philips minus FFDM) in recall rates 
among non-cancers is less than 0.05 (delta of 5%), Philips tomosynthesis will be considered as 
resulting in a similar recall rate to that of 2D FFDM.  In addition, a bootstrapping method with 
replacement will be used to compare average recall rates among all Readers. 
The sensitivity or specificity within a reader between the two systems will be estimated, and tested for 
statistical significance using binomial test for paired data. Results will be summarized across readers 
using the ANOVA model of Obuchowski and Rockette [11], which applies to any metric of diagnostic 
accuracy under general conditions. The following hypothesis will be evaluated: 
 
Null Hypothesis: Ho:  S2 - S1 ≥ 0.10 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 31 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
 
Alternative Hypothesis:  S2 - S1 < 0.10 
Where S1 is average sensitivity/specificity for readers using the Philips MicroDose tomosynthesis 
system and S2 is the average sensitivity/specificity for readers using the FFDM.  The Philips 
MicroDose tomosynthesis system will be considered non-inferior to the FFDM if the upper limit one-
sided 95% CI for the difference in sensitivity/specificity is less than 0.10. 
To evaluate the effect of breast density on ROC AUC for images obtained using Philips MicroDose 
tomosynthesis system and FFDM, breast density will be stratified as fatty (i.e., BI-RADS breast density 
type A and B) and dense (BI-RADS breast density type C and D).  Analysis will be similar to the 
described for the primary efficacy analysis.  
 
6.9. 
Supplementary Efficacy Analysis 
The following supplementary objectives will be evaluated: 
 
To evaluate the effect of breast density on ROC AUC for images obtained using Philips 
MicroDose tomosynthesis system and FFDM system. Breast density will be stratified as fatty 
(i.e., BI-RADS breast density type 1 and 2) and dense (BI-RADS breast density type 3 and 
4). 
 
To compare the average image interpretation time for exams performed with Philips 
MicroDose SI Tomosynthesis and the FFDM system. 
 
To assess the diagnostic performance of the Philips MicroDose Tomosynthesis compared to 
FFDM  
To evaluate the effect of breast density on ROC AUC for images obtained using Philips MicroDose 
tomosynthesis system and FFDM, breast density will be stratified as fatty (i.e., BI-RADS breast density 
type A and B) and dense (BI-RADS breast density type C and D).  Analysis will be similar to the 
described for the primary efficacy analysis.  
 
The diagnostic performance of the Philips MicroDose Tomosynthesis compared to the FFDM will be 
assessed using the free-response receiver operating characteristic (FROC) paradigm.  The analysis 
will use Confidence score for each suspicious focus, along with its location relative to any biopsy-
proven malignancy; and will allow multiple suspicious foci per-case.  Analysis will be performed using 
JAFROC (jackknife AFROC) as described by Chakraborty and Berbaum  (2004). Truth will be 
established by a MQSA qualified radiologist. 
7. 
DATA MANAGEMENT 
7.1. 
Access to Source Documents 
Study records, including each subject’s signed informed consent, and other study-related documents 
pertaining to the conduct of the study will be kept in a secure area.  Subject information will remain 
confidential.  However, consent forms, medical history and image records that identify subjects may be 
inspected by the sponsor, its authorized designees and regulatory agencies including but not limited 
to, the Department of Health and Human Services (DHHS), the United States Food and Drug 
Administration (FDA), other foreign regulatory bodies and the Institutional Review Board/Ethics 
Committee for this study.  Because of the need to release information to these parties, absolute 
confidentiality cannot be guaranteed. The results of this research project may be presented at 
meetings or in publications; however, subject identity will not be disclosed in such publications. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 32 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
7.2. 
Retention period 
The sponsor and investigator shall maintain the records related to this study during the investigation 
and for a period of 5 years after the latter of the following two dates: The date on which the Research 
is terminated or completed, or the date that the records are no longer required for purposes of 
supporting a premarket approval application in the US or a notice of completion of a product 
development protocol. Or longer if national regulation requires this. 
The sponsor and principal investigator shall take measures to prevent accidental or premature 
destruction of these documents. 
7.3. 
Data Management 
Data will be collected in a case report form (CRF) and transcribed in a central database system or in 
an electronic CRF (eCRF). After the data are entered in the database, edit checks, programmed to 
ensure the collection of consistent and complete data, may be raised.   
In addition, Philips (or contracted) Monitors, Project Statistician, and/or the Philips data management 
group will review data listings generated at different time points during the study. Data queries will be 
generated to resolve any discrepancies or concerns.   
Additionally, Data transcribed to the CRFs will be source data verified by the Sponsor/designee(s) on 
a percentage of the subject population (e.g., 10% or more as appropriate per a risk-based monitoring 
approach).  Data queries will be generated to resolve any discrepancies or concerns. 
It is the responsibility of the Site designated personnel to respond to all edits checks and queries.  
Submitted data as well as all data modifications to submitted data will be documented by the system 
and available in audit trails. 
Upon conclusion of the study, after all data are marked as complete and all discrepancies are 
resolved, the Principal Investigator will be notified to review and sign the case books.  Subsequently, a 
member of the Philips Health Management Group or designee will lock the database. The final data 
set will be transferred to SAS for analysis at Philips.   
8. 
DEVICE ACCOUNTABILITY 
Access to the investigational device shall be controlled and the investigational devices shall be used 
only in accordance with the clinical investigational plan and the contract with the sites. 
The sponsor shall keep records to document the physical location of all investigational devices from 
shipment of investigational device to the Research sites until de-installation. 
9. 
INFORMED CONSENT PROCESS 
Informed consent will be obtained from every subject in writing by the Investigator or his authorized 
designee before the clinical trial is started. The subject will be informed both orally and in writing about 
all aspects that are relevant to the subject’s decision to participate in the trial, including the trial 
procedures and risks and benefits of participation in the clinical trial. Ample time should be provided 
for the subject to read and understand the informed consent form and to consider participation. The 
informed consent will include personally dated signatures of the subject and the principal investigator 
or an authorized designee responsible for conducting the informed consent process. A copy of the 
signed and dated informed consent form and any other written information will be provided to the 
subject. 
Subjects who are unable or unwilling to provide informed consent will not be included in the trial. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 33 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
If new information becomes available that might significantly affect the subject’s future health and 
medical care, it shall be provided to the subjects in written form. If relevant, subject shall be asked to 
reconfirm their continuing informed consent in writing. 
The patient information and consent will follow the guidelines set forth in the Code of Federal 
Regulations (21 CFR 50) and ISO 14155 for patient information and informed consent. To be eligible 
for enrollment in the study, all subjects or their authorized representatives must first understand and 
sign a patient information and consent form approved by the study center's Institutional Review Board 
/ Ethics Committee or provide informed consent verbally when allowed by IRB/EC. 
10. 
ADVERSE EVENT REPORTING 
An Adverse Event (AE) is defined as any untoward medical occurrence, unintended disease or injury 
or any untoward clinical signs (including an abnormal laboratory finding) in subjects, users or other 
persons whether or not related to the investigational device. 
NOTE 1: This definition includes events related to the investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to investigational medical 
devices. 
 
An Adverse Device Effect (ADE) is defined as an adverse event related to the use of a medical device. 
This includes any adverse event resulting from insufficiencies or inadequacies in the instructions for 
use, the deployment, the implantation, the installation, the operation, or any malfunction of the medical 
device, and any event that is a result of a use error or intentional misuse. 
 
An AE or ADE is classified as serious when: 
- 
it results in death 
- 
it is life threatening 
- 
it requires inpatient hospitalization or prolongation of existing hospitalization 
- 
it results in persistent or significant disability/incapacity 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the Clinical Investigational 
Plan, without serious deterioration in health, is not considered a serious adverse event. 
 
Unanticipated adverse device effect (UADE) means any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the investigational 
plan or application (including a supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects. 
10.1. 
Complaint 
Any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, 
durability, reliability, safety, effectiveness, or performance of a device after it is released for 
distribution. 
 
A security event is defined as an observable occurrence leading to either or both of the following: 
 
Software or any data that are managed by a PH product are suspected of being maliciously 
altered, misused or lost (includes virus, worm, hackers, etc.); and/or 
 
A system or component has a customer-reported security vulnerability that could result in 
alteration, misuse or loss.  
The investigator shall report any related or unrelated serious adverse (device) event within 48 hours to 
the sponsor and IRB/EC and shall be confirmed by using the adverse event form within one week. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 34 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
Non-serious adverse (device) events shall be recorded on the adverse event forms. The Sponsor and 
Monitor can request access to this information at any time. 
10.2. 
Reporting 
The investigator shall report via the adverse event form in the CRF any anticipated and unanticipated 
adverse device effects to the sponsor in a timely manner.  
The investigator shall report any complaint via the device deficiency form. 
An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated 
adverse device effect occurring during the study as soon as possible, but in no event later than 10 
working days after the investigator first learns of the effect. 
The Sponsor and Monitor can request access to this adverse event information at any time. 
Please see Appendix II: List of monitor(s) for emergency contact for reporting UADE. 
The CRF will include the following information for adverse events: date of the adverse event, 
description, actions taken, resolution, assessment of both the seriousness and the relationship to the 
Philips MicroDose Tomosynthesis and procedure. Information collected for device deficiencies are: 
date of device deficiency, whether this could have led to a Serious Adverse Device Effect (SADE) if a) 
suitable action had not been taken or b) intervention had not been made or c) if circumstances had 
been less fortunate.  
10.3. 
Anticipated and unavoidable adverse device effects  
Anticipated adverse device effects are described below in Table 5.  
Table 5:  Anticipated adverse device effects 
Anticipated adverse device 
effects 
Likely incidence 
Mitigation or Treatment 
Pinch or cut injury 
Not likely 
Treatment of injury 
Loss of images 
Not likely 
Retake of image or patient 
excluded from study 
Collision with rotating C-arm 
Not likely 
Treatment of injury 
Image artefacts 
Not likely 
Retake of image or patient 
excluded from study 
 
The following unavoidable adverse events are very common according during the procedures 
performed in this clinical trial. Unavoidable adverse events do not need to be reported.  
Table 6: Unavoidable adverse events 
Unavoidable adverse event 
Time frame 
Discomfort due to compression 
During examination 
11. 
EARLY TERMINATION OR SUSPENSION OF THE RESEARCH 
There are no provisions or interim analyses planned that can result in an early termination of the trial.  
Any signs of unknown or increased risks for the subjects will be discussed by the sponsor and 
investigator to assess the impact on the subjects and clinical research. Serious or repetitive 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 35 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
occurrence of deviations from study protocol or non-compliance with regulations may also be reason 
for early termination or suspension of a study site.  
12. 
PUBLICATION POLICY 
This study will be registered on clinicaltrials.gov before first enrollment. Results from the study may be 
published in peer reviewed journals and presented at scientific conferences. Study sites may use data 
from the study for other research as long as they have prior agreement with the study sponsor and 
have IRB approval as appropriate.  
 
13. 
REFERENCES 
[1] Surveillance Research Program. Lifetime risk of breast cancer. in National Cancer Institute [database 
online]. Washington, DC, 2009Available from http://seer.cancer.gov/studies/surveillance/study7.html 
(accessed May 16, 2009).  
[2] Feig, S. A., G. S. Shaber, G. F. Schwartz, A. Patchefsky, H. I. Libshitz, J. Edeiken, R. Nerlinger, R. F. 
Curley, and J. D. Wallace. 1977. Thermography, mammography, and clinical examination in breast 
cancer screening. review of 16,000 studies. Radiology 122, (1) (Jan): 123-7.  
[3] The Swedish Organized Service Screening Evaluation Group. Duffy SW, Tabar L, Tony H.H. Chen et 
al. Reduction in Breast Cancer Mortality from Organized Service Screening with Mammography: 1. 
Further Confirmation with Extended Data. Cancer Epidemiol Biomarkers Prev 2006;15(1):45-51 
[4] Skaane P, Young K, Skjennald A.: “Population-based mammography screening: comparison of 
screen-film and full-field digital mammography with soft-copy reading--Oslo I study.” Radiology. 2003 
Dec; 229(3):877-84. Epub 2003 Oct 23 
[5] Skaane P. and Skjennald A.: “Screen-Film Mammography versus Full-Field Digital Mammography with 
Soft-Copy Reading: Randomized Trial in a Population-based Screening Program--The Oslo II Study” 
Radiology, July 1, 2004; 232(1): 197 - 204. 
[6] Etta D. Pisano, M.D. et al.: Diagnostic Performance of Digital versus Film Mammography for Breast-
Cancer Screening, New England Journal of Medicine 2005; 353 
[7] Houssami N, Skaane P.: Overview of the evidence on digital breast tomosynthesis in breast cancer 
detection. Breast. 2013 Apr; 22(2):101-8. doi: 10.1016/j.breast.2013.01.017 
[8] Hardesty et al, Digital Breast Tomosynthesis Utilization in the United States: A Survey of Physician 
Members of the Society of Breast Imaging., J Am Coll Radiol. 2014 Apr 5. pii: S1546-1440(13)00807-
7. doi: 10.1016/j.jacr.2013.11.025. [Epub ahead of print] 
[9] Spectral tomosynthesis breast density validation - reader study protocol, DOC-JREN-9LYJYC 
[10] Dorfman DD, Berbaum KS, Metz CE. Receiver Operating Characteristic Rating Analysis: 
Generalization to the Population of Readers and Patients with the Jackknife Method. Investigative 
Radiology 1992; 27:723-731. 
[11] Obuchowski NA, Rockette HE. Hypothesis testing of diagnostic accuracy for multiple observers and 
multiple tests: an ANOVA approach with dependent observations. Comm Stat 1995; 24:285-308 
[12] OR-DBM MRMC 2.4 http://perception.radiology.uiowa.edu/Software/ReceiverOperating 
CharacteristicROC/MRMCAnalysis/ORDBMMRMCDownloads/tabid/160/Default.aspx 
[13] Hillis SL, Obuchowski NA, Schartz KM, Berbaum KS. A comparison of the Dorfman-Berbaum-Metz 
and Obuchowski-Rockette Methods for receiver operating characteristic (ROC) data. Statistics in 
Medicine 2005; 24:1579-1607. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 36 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
[14] Hillis SL. A comparison of denominator degrees of freedom methods for multiple observer ROC 
analysis. Statistics in Medicine 2007; 26:596-619 
[15] Hillis SL, Berbaum KS, Metz CE. Recent developments in the Dorfman-BerbaumMetz procedure for 
multireader ROC study analysis. Academic Radiology2008; 15:647-661 
[16] Beam, Layde and Sullivan. Variability in the Interpretation of Screening Mammograms by US 
Radiologists, Findings from a National Sample. Arch Intern Med 1996; 156(2):209-213 
[17] Obuchowski NA. Sample size tables for receiver operating characteristic studies. AJR Am J 
Roentgenol 2000; 175(3):603-8 
[18] Rockette, Campbell, Britton Holbert, King and Gur. Empiric assessment of parameters that affect the 
design of multireader receiver operating characteristic studies. Academic Radiology 1999; 6:723-729 
[19] Statistics Collaborative, Inc. Protocols DOC-SRYL-7VN99P and DOC-SRYL-7W5FTC Sectra 
MicroDose Mammography L30: Accuracy and Feature Analysis for the Multi-Reader, Multi-Case 
Comparison of the Sectra MicroDose Mammography L30 to the GE Digital Mammography System. 
June 6, 2011 
[20] Hologic, Inc. P080003/S001 Hologic Selenia Dimensions 3D System, FDA Executive Summary. Oct 
24, 2012. 
[21] Gallas BD, Chan HP, D'Orsi CJ, Dodd LE, Giger ML, Gur D, Krupinski EA, Metz CE, Myers KJ, 
Obuchowski NA, Sahiner B, Toledano AY, Zuley ML. Evaluating imaging and computer-aided 
detection and diagnosis devices at the FDA. Acad Radiol. 2012 Apr; 19(4):463-77. doi: 
10.1016/j.acra.2011.12.016. Epub 2012 Feb 3. PubMed PMID: 22306064. 
[22] Dmitrienko, A.; Tamhane, A. C.; Bretz, F. Multiple Testing Problems in Pharmaceutical Statistics. 
Chapman & Hall/CRC Biostatistics Series, 2007, 320pages. 
[23] P. Chakraborty, P., and  Berbaum , K. S.  Observer studies involving detection and localization: 
Modeling, analysis, and Validation. Med. Phys. 37, 5054 (2004): 2313 – 2330. 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 37 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
APPENDIX I: LIST OF INVESTIGATORS AND SITES 
 
Update of this list can be provided to the Research site under separate cover. 
Table 1: List of principal Investigators 
Name Principal Investigator(s) 
Name and address investigation site(s) 
Etta Pisano, M.D. 
N/A 
 
 
 
 
 
 
 
 
 

 
Philips 
Mammography 
Solutions 
Sweden 
 
Clinical Investigation Plan 
Comparison of the Philips MicroDose 
Tomosynthesis System to 2D Digital 
Mammography 
DOC-MTIN-9RWH8K-
8.0 
Page 38 of 38 
 
 
 
Template ID: DOC-EMOA-8TFF4K / 2013 
Philips' proprietary information. Unauthorized use is prohibited. 
 
APPENDIX II: LIST OF MONITOR(S)/CLINICAL SCIENTIST 
 
Update of this list can be provided to the Investigational sites under separate cover. 
Table 2: List of monitor/clinical scientist 
 
Name Monitor(s)/Clinical Scientist 
Contact Information of Monitors 
Ingrid Schulze-Wenck 
 
Hamburg, Germany, 
Telephone:  +49 40 5078-1750 
Mobile:    +49 172 299 88 73 
ingrid.schulze-wenck@philips.com 
Elin Moa 
Solna, Sweden 
Telephone: +46 8 623 52 00 
Elin.moa@philips.com