Comparison of Full-Field Digital Mammography With Digital Breast Tomosynthesis Image Acquisition in Relation to Screening Call-Back Rate
Phase: NA
Conditions: Breast Neoplasms
Sponsor: American College of Radiology

 
 
ACRIN PA 4006 
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June 14, 2010 
 
AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK 
 
ACRIN PA 4006 
 
Comparison of Full-Field Digital Mammography with Digital Breast Tomosynthesis  
Image Acquisition in Relation to Screening Call-Back Rate 
 
 
Study Chair 
 
Emily F. Conant, MD 
Breast Imaging 
Department of Radiology 
Hospital of University of Pennsylvania 
3400 Spruce Street 
Philadelphia, PA 19118 
Phone: 215-662-4 032 
Fax: 215-456-7578 
Email: emily.conant@uphs.upenn.edu
 
Co-Chair 
Andrew Maidment, MD, FAAPM 
Chief, Physics Section 
Department of Radiology – 1 Silverstein 
Hospital of the University of Pennsylvania 
3400 Spruce Street 
Philadelphia, PA 19104 
Phone: 215-746-8763 
Fax: 215-746-8764 
Email: Andrew.Maidment@uphs.upenn.edu
 
Co-Chair 
Debra Somers Copit, MD 
Director, Breast Imaging 
Albert Einstein Medical Center 
Assistant Professor of Radiology 
Jefferson Medical College 
Phone: 215-456-6250 
Fax: 215-662-7436 
Email: copitd@einstein.edu
 
Study Statistician 
Constantine Gatsonis, PhD 
Center For Statistical Sciences 
Brown University, Box G-S121-7 
121 South Main Street 
Providence, RI 02912 
Phone: 401-863-9183 
Fax: 401-863-9182  
Email: gatsonis@stat.brown.edu
 
 
Original Date: June 14, 2010 
Activation Date: TBD 
 
CONFIDENTIAL 
 
This protocol was designed and developed by the American College of Radiology Imaging 
Network (ACRIN). It is intended to be used only in conjunction with institution-specific 
IRB approval for study entry. No other use or reproduction is authorized by ACRIN, nor 
does ACRIN assume any responsibility for unauthorized use of this protocol. 

CONFIDENTIAL 
 
Table of Contents  
 
Schema 
 
1.0 
Abstract..................................................................................................................................5 
 
2.0  
Background and Significance ................................................................................................6 
 
3.0 
Study Objectives/Specific Aims ............................................................................................9 
 
4.0 
Study Overview .....................................................................................................................10 
 
5.0 
Participant Selection/Eligibility Criteria................................................................................11 
 
6.0 
Site Selection .........................................................................................................................12 
 
7.0 
Data Management/Online Registration..................................................................................14 
 
8.0  
Study Procedures ...................................................................................................................17 
 
 
9.0  
Imaging and Reader Studies Protocols ..................................................................................22 
 
 
10.0  Adverse Events Reporting .....................................................................................................23 
 
11.0  Ethical Considerations ...........................................................................................................28 
 
12.0  Conflict of Interest.................................................................................................................28 
 
13.0  Publication Policy..................................................................................................................28 
 
14.0  Institutional Monitoring and Audits.......................................................................................29 
 
15.0  Statistical Considerations ......................................................................................................31 
 
References..........................................................................................................................................34 
 
Appendix I: 
Informed Consent Form Template.............................................................................35 
 
Appendix II: Supplemental Materials Available Online.................................................................44 
 
 
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CONFIDENTIAL 
 
 
AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK 
 
ACRIN PA 4006: Comparison of Full-Field Digital Mammography with Digital Breast 
Tomosynthesis Image Acquisition in Relation to Screening Call-Back Rate 
 
SCHEMA 
RECRUIT PRE-IMAGING: Group A 
500 Screening Participants 
Screening Imaging 
FFDM* (images to be delivered to ACRIN) 
RECRUIT PRE-IMAGING: Group B 
50 Participants Called Back  
STUDY IMAGING: Screening 
Clinical FFDM 
+ 
Study Tomo Imaging 
After Screenin
 
 
 
Clinical FFDM, full-field digital mammography; Study Tomo Imaging, two-view tomosynthesis plus low-dose MLO 
(mediolateral oblique) and low-dose CC (cranial caudal) views; US, ultrasound.  
*  The screening digital mammography that prompted the recommendation for call back for potential Group B participants 
will have to be available for submission to ACRIN for patients to qualify for participation in the Group B arm. 
† “Image Positive” abnormal findings from either FFDM or tomosynthesis image set on-site clinical reads will be used to 
trigger call back of participants for diagnostic assessment. 
g 
STUDY IMAGING: Diagnostic  
Call-Back Diagnostic Imaging 
(FFDM +/- US, Other) 
+ 
Study Tomo Imaging 
On-Site Clinical Read 
Readers randomly assigned images to 
assess and blinded to complementary 
imaging to determine call backs† 
+
On-Site Sequential Clinical Read 
Screening + Diagnostic FFDM  
then  
Tomo with low-dose MLO only 
+ 
Low-dose CC 
+ 
US and/or Other (if applicable)
Follow Up to 18 Months 
After Screening 
Follow Up to 18 Months 
After Screening 
Image Positive† 
Call back for diagnostic 
Image Negative 
No call back 
MONITORING 
(LESION TYPE) 
Diagnostic Imaging 
Standard of Care 
(FFDM +/- US, Other) 
ADJUDICATION OF IMAGES: Image positive cases (call-back cases), as well as 
any interval cancers, will be adjudicated by lesion type so that sub-analyses may 
be performed comparing image sequences across lesion subtypes. 
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CONFIDENTIAL 
 
 
SPECIFIC HYPOTHESES  
This multicenter trial using Hologic digital mammography units will evaluate the specificity of 2-D full 
field digital mammography (FFDM) versus a combination of 2-D and 3-D tomosynthesis imaging in 
breast cancer screening. Specificity, in this study, will be measured by the participant call-back rate by 
each modality. Varying combinations of 2-D mammography and tomosynthesis projections will be 
evaluated to optimize the screening paradigm and limit radiation exposure when tomosynthesis is 
incorporated. Both prospective and retrospective imaging data will be assessed.     
1. Digital breast tomography (DBT) will improve the specificity of breast cancer screening as 
measured by a reduction in the call-back rate while maintaining the sensitivity of cancer detection. 
This improved accuracy will be achieved by the optimization of the imaging sequence and number 
of views obtained at a capped radiation dose in the combined DBT and 2-D screening sequence.  
 
 
Asymptomatic women 25 years and older with no history of breast cancer will be recruited from a 
prospective population of patients scheduled for screening mammography (Group A). A similar 
population of women called back from screening for 2-D FFDM-detected abnormalities will also be 
recruited to provide an enriched population of true-positive and false-positive 2-D FFDM and 
tomosythesis cases (Group B). Pregnant women, women unable to tolerate compression of the breast 
associated with mammography, women with implants, and women with breasts too large to 
accommodate adequate positioning of the breast for DBT are excluded from trial participation. 
ELIGIBILITY (see Section 5.0 for details) 
 
 
SAMPLE SIZE  
A total of 500 participants will be recruited for collection of prospective imaging data in this trial 
(Group A); 50 additional participants, recalled for diagnostic assessment after positive screening 
findings, will be recruited for DBT imaging data collection and retrospective image analysis (Group B). 
Participating institutions for this trial will be clinical research institutions in Pennsylvania with Hologic 
tomosynthesis units. 
 
 
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1.0 
ABSTRACT  
This protocol for human research study is conducted according to United States and international 
standards of Good Clinical Practice (International Conference on Harmonisation [ICH] Guidelines), 
applicable government regulations (e.g. Title 45, Part 46 Code of Federal Regulations) and the 
American College of Radiology Imaging Network (ACRIN) research policies and procedures. 
 
The incorporation of tomosynthesis, a novel 3-D reconstruction of multiple low-dose digital 
mammographic images may reduce the number of diagnostic examinations (call-back visits) needed by 
providing many of the benefits of diagnostic imaging during screening. The results of early studies of 
tomosynthesis technology are promising and indicate that the specificity of screening mammography 
can be improved with the incorporation of digital breast tomosynthesis (DBT) without concomitant loss 
in overall sensitivity.1–3 Unfortunately, the peer-reviewed publications evaluating DBT in the screening 
setting are limited and consist of single institution/single manufacturer studies with a small number of 
patients. Additionally, the optimal procedural metrics in DBT have not been fully defined. 
Manufacturers have different platforms that offer different combinations of tomosynthesis projections 
(mediolateral oblique [MLO] only versus MLO plus cranial caudal [CC]), different tomosynthesis image 
acquisition geometries (angular range, number of projections, dose distribution across projections, 
detector and tube motion, etc.), and different radiation dose levels (one to two times the dose of a 
mammogram). Controversy continues over the use of tomosynthesis in combination with 2-D FFDM or 
as a stand-alone—tomosynthesis only—screening method without concomitant 2-D imaging. This 
disparity in image number and image acquisition parameters may alter the balance between specificity 
and sensitivity and significantly affect radiation dose.   
 
Studies have shown that tomosynthesis is effective in characterizing possible masses, focal asymmetries, 
and areas of architectural distortion seen on 2-D mammography. However, the lower conspicuity of 
calcifications with tomosynthesis than on 2-D mammography has been a concern and may stem from 
several factors that need to be explored.1,4 Standard 2-D FFDM projection images summate all the 
calcifications in a cluster in a single-image presentation, potentially allowing improved detection and 
characterization of calcified lesions. In DBT, calcifications are presented on individual image slices 
rather than as a summated cluster and may therefore be more difficult to detect and characterize than on 
conventional projection imaging. While post-processing algorithms including slab reconstruction and 
novel 3-D computer aided detection (CAD) programs may potentially improve the conspicuity of 
calcifications in tomosynthesis, these programs are still under development.1,3,4 In addition, movement 
of the tube during tomosynthesis image acquisition may lead to blurring of the fine detail of 
calcifications necessary for accurate characterization.1 Similarly, long total scan time may result in 
patient motion which can blur the fine detail of calcifications.    
 
This study will assess variations in DBT image acquisition while limiting radiation dose to participants 
with varying breast sizes and densities. The expected outcome of this research is to show, with the 
incorporation of tomosynthesis in the screening paradigm, a reduction in the number of false-positive 
interpretations without a loss of cancer detection. This improvement in screening specificity can be 
gained while limiting both the number of imaging views and the radiation dose to the participant.  
 
 
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2.0 
BACKGROUND AND SIGNIFICANCE 
2.1 
Current Breast Screening and the Tomosynthesis Advantage 
With competing parameters of specificity and sensitivity, breast cancer screening must limit both missed 
cancers and false-positive call-backs (with potential to biopsy) to reduce cost and unnecessary anxiety in 
patients. FFDM has been shown to provide improved sensitivity over analog mammography in the 
detection of breast cancers, particularly in women with dense breasts.5 Unfortunately, the call-back rates 
for both digital and analog screening mammography remain elevated with similar rates of approximately 
10%.5 This results in many women receiving additional imaging of “pseudo-lesions” or suspicious-
looking superimpositions of glandular tissue on 2-D projection imaging that additional imaging later 
proves to be normal. Advanced techniques have been proposed that make use of the additional 
capabilities of digital image processing inherent to digital mammograms.6 
 
Screening mammography examinations are performed currently by taking 2-D projection images of the 
breast, while tomosynthesis involves taking multiple low-dose images at sequential angles that are 
reconstructed and presented as a 3-D image set of the breast. DBT has been proposed for both diagnostic 
and screening applications since the 3-D image set provides a presentation in which the effects of tissue 
superposition are largely removed from the image, as superimposed tissue may hide breast cancers. The 
ability to “scroll through” the sequential slices of the 3-D reconstructed breast images in DBT can 
contribute to improved conspicuity of cancers and avoid the creation of spurious lesions due to 
superposition of overlying and underlying tissue structures. The reduction of superimposed tissue should 
allow the detection of cancers that may be hidden by superimposed normal breast tissue.1–4,6 
 
The radiation doses from tomosynthesis can be similar to those from conventional projection (2-D) 
imaging, thus tomosynthesis has the potential to replace conventional mammograms while improving 
both sensitivity and specificity of cancer detection. A screening tomosynthesis examination may reduce 
the number of diagnostic exams needed by essentially providing many of the benefits of diagnostic 
imaging in the screening examination. 
 
2.2 
Screening and Diagnosis With FFDM and/or Tomosynthesis:  
Disparities, Unanswered Questions, and the Need for Further Evaluation 
Studies have shown that tomosynthesis is effective in identifying masses and areas of architectural 
distortion. However, visibility of calcifications, an early indicator of breast cancer, with tomosynthesis 
has been a concern and stems from several factors that need to be explored.1,4 Standard 2-D projection 
images summate all the calcifications in a cluster in a single-image presentation, potentially allowing 
improved detection and characterization of calcified lesions. In a tomosynthesis image set, calcifications 
are presented on individual image slices rather than as a summated cluster and may therefore be more 
difficult to detect and characterize than on conventional projection imaging. In addition, during 
tomosynthesis image acquisition, incremental movement of the tube over an angle may lead to blurring 
of the fine detail of calcifications necessary for accurate characterization. Multiple images of 
calcifications, taken over a large angular range, may reduce the fine detail or edge characteristics of 
calcifications.  
 
Two general techniques are currently used for acquiring the tomosynthesis image set. One technique 
acquires images with the tube in continuous motion over an arc of approximately 15 degrees. The 
approach requires very rapid x-ray exposures so that blurring of the tomosynthesis image is minimized. 
In this scenario, the length of time the patient’s breast is in compression is minimized, thereby reducing 
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patient motion. The second technique is a “step and shoot” technique where the tube stops along the arc 
for each image acquisition. This approach eliminates blurring from the x-ray source/tube, but requires 
longer breast compression, resulting in the potential for greater breast motion, also causing blurring.1 
The first feature that may be lost with blurring is the visibility of calcifications.  
 
Full-Field Digital Mammography. Rothenberg et al7 reviewed records from the Blue Cross Blue 
Shield Association Technology Evaluation Center after updates from the Oslo II study8 and ACRIN 
6652 Digital Mammographic Imaging Screening Trial (DMIST),5,9 a trial providing more than 42,000 
cases of FFDM and film-screen mammography. These studies found the two modalities to be largely 
equivalent in screening accuracy, but with greater cancer detection with FFDM among specific 
populations of women for whom breast cancer is more difficult to detect with film-screen 
mammography. FFDM appeared to have greater accuracy among women stratified for age (ACRIN 
6652 DMIST: women younger than 50; Oslo II: women ages 50 to 69), menopausal status (pre-
menopausal or perimenopausal), and breast density (heterogeneous or extremely dense breasts). Both 
modalities face limitations from false-positive results. From a diagnostic point of view, Rothenberg et al 
infer FFDM detected more invasive carcinomas and medium-grade to high-grade ductal carcinomas in 
situ. FFDM has many other advantages over film-screen mammography which include: the ability to 
electronically archive and transmit images, the ability to post-process images to enhance the conspicuity 
of some lesions types, and the ability to apply computer-aided detection (CAD) algorithms to assist 
radiologists in the detection of breast lesions. 
 
Tomosynthesis. The promise of DBT in the screening setting is its potential to reduce false-positive 
call-back examinations, without a loss of sensitivity over conventional digital mammography. The 
results of early studies are promising and indicate that the specificity of DBT is improved without 
concomitant loss in overall sensitivity.1–5 In 2007, Poplack et al1 compared the image quality of 
tomosynthesis imaging as an adjunct to diagnostic imaging with film-screen mammography for 
participants who had been called back from screening. In this reader study, the tomosynthesis images 
were considered “comparable-to-superior” in image quality to the diagnostic 2-D imaging in 89% of 
cases. In addition, it was determined that approximately half (52%, or 52 of 99) of these women would 
not have been called back for diagnostic imaging had their screening been conducted using FFDM 
supplemented with tomosynthesis. After adjustment, reduction in call back was determined to be 40%. 
Further assessment determined significant correlation between call back and tumor type (p = 0.004). In 
addition, tomosynthesis performed better than 2-D mammography for the detection and characterization 
of all lesions types except for calcifications. The 2-D mammography outperformed tomosynthesis in the 
evaluation of calcific lesions on the basis of better conspicuity and better discrimination of calcium 
particle number and morphology. This finding was thought to be due to a combination of image blur and 
image presentation in DBT, where slices were reconstructed at too thin a slice to allow the observer to 
perceive the clustering of the calcifications.1  
 
Few published trials on breast cancer screening with tomosynthesis exist, partly because the optimal 
procedural metrics for tomosynthesis have not been fully defined. A multi-institutional screening trial 
was presented in 2007 (in abstract form only) by Rafferty2, which recruited 1,083 women from five 
clinical sites for 2-D FFDM plus DBT. From the data set, 316 imaging data sets were selected randomly 
to create an enriched reader study with 12 radiologists. The receiver operating characteristic (ROC) for 
all 12 radiologists was superior for FFDM plus DBT that for FFDM alone. The specificities for the 
reader increased from 84.1% to 89.2%, and the sensitivity improved from 65.5% to 76.2%. A mean 
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reduction in call-back rate of 42.6% was also observed.2 In this combination of 2-D FFDM plus DBT, 
the combined radiation dose per breast is estimated to be approximately 5.8 mGy, which is twice the 
dose of a routine mammogram performed on the same equipment and significantly higher than the 
national average dose for routine two-view mammogram (3.4 mGy).  
 
The optimal procedural metrics for DBT have not been fully defined, thus limiting scientifically sound, 
practice-guiding results. Manufacturers have different platforms that offer different views (MLO only 
versus combination MLO plus CC), different tomosynthesis image acquisition geometries, and different 
radiation dose levels. The exact number of tomosynthesis views of MLO only or combination MLO-
and-CC tomosynthesis views varies. Controversy continues over the use of tomosynthesis with 2-D 
FFDM or its use as a stand-alone screening method. This disparity in image number and image 
acquisition parameters may alter the balance between specificity and sensitivity and significantly affect 
radiation dose. The current study design focuses on optimizing image quality with reduced call-back 
rates while limiting radiation dose. 
 
2.3 
Screening With FFDM and/or Tomosynthesis:  
Collecting Beneficial Images While Limiting Radiation Exposure 
The disparity in image number and image-acquisition parameters may alter the balance between 
specificity and sensitivity, and significantly affect radiation dose. While tomosynthesis shows promise in 
its potential to more accurately diagnose questionable lesions as malignant or not, the potential increase 
in radiation exposure from this technology in comparison with ultrasound or magnetic resonance 
imaging (MRI) calls into question the risk over benefit of this imaging advance. 
 
The national average dose per breast for two-view 2-D mammography is 3.4 mGy. The exact dose varies 
by manufacturer and technology (film-screen, computed radiology, and direct radiology). We propose to 
investigate the use of a dose for the complete tomosynthesis image set (two-view tomosynthesis at 
approximately 1.2 mGy each, plus two simultaneously-acquired, low-dose 2-D combination 
tomosynthesis plus set views at approximately 1.0 mGy each) of 4.4 mGy, which is comparable to 
conventional mammography. The dose for the “limited tomosynthesis set” of two-view tomosynthesis 
plus low-dose 2-D MLO only is approximately 3.4 mGy, equal to routine two-view mammography. The 
addition of the CC view—the added benefits of which will be assessed in the course of this trial—
contributes approximately 1.0 mGy of exposure. This trial will limit the potential radiation exposure to 
determine the quality of the images obtained with these varying combinations of views. Local reader 
evaluations, as well as an adjudication process, will include assessment for image quality and 
completeness for analysis. 
 
2.4 
Defining the Questions to Determine the Answers 
The potential of tomosynthesis cannot be clearly defined until optimal, standardized technical 
parameters, angle views, and low-dose radiation exposure can be determined. Among asymptomatic 
women being screened with FFDM, this trial will assess the combinations of views between 
variations—two-view tomosynthesis with a low-dose 2-D MLO with and without CC view in 
comparison with institutional standard-of-care two-view FFDM—to determine prospective call-back 
rates at the sites of accrual.  
 
Among an enriched population of women called back for diagnostic imaging based on positive findings 
during previous screening with FFDM, diagnostic imaging will include DBT (to both breasts, even if 
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only a single breast was found suspicious during screening assessment) to determine its impact on 
defining true-positive and false-positive disease findings. Lesions types based on screening FFDM 
findings will be characterized at a basic level to classify them for monitoring—as calcification-only or 
as soft-tissue lesions (masses, asymmetries, architectural distortions, or masses with calcification)—to 
evaluate DBT’s capacity to characterize “calcification only” lesions as compared to FFDM. The 
assumption is that most Group A call-back cases will comprise soft-tissue lesions. Therefore, the 
enrollment to the Group B enriched population will be targeted to first accrue calcification-only lesion 
cases. Recruitment to Group B may be adjusted to include soft-tissue cases to achieve target accrual 
while targeting a final 75/25-to-50/50 ratio (e.g., 75 soft-tissue to 25 calcification-only lesions; ratio 
based on ACRIN 6652 DMIST data; see Section 6.4 for more detail). 
 
An analysis will be performed to compare the appropriate combination of images for the tomosynthesis 
set to cap the per-breast dose at approximately 3.4 mGy (equivalent to 2-D mammography). 
Determining the quality and value of tomosynthesis image sets with limited radiation exposure is an 
integral part of the trial’s objectives. The potential benefit of tomosynthesis imaging within the 
appropriate population of people at risk for breast cancer can be achieved only by proving the value of 
characterization of suspicious findings using tomosynthesis and reducing the risk associated with higher 
radiation doses currently associated with the technology.  
 
Because this trial is limited to Pennsylvania-based institutions—and therefore to Hologic imaging 
technology only—due to funding requirements, subsequent assessment of technical parameters across 
manufacturers will need to follow in a multi-center national trial. 
 
 
3.0 
STUDY OBJECTIVES/SPECIFIC AIMS  
ACRIN PA 4006 is designed to answer questions related to image combinations and quality in pursuit of 
reduced radiation exposure from tomosynthesis technology. 
 
3.1 
Primary Aim  
3.1.1 To compare recall rates of FFDM to the limited DBT set (digital breast two-view 
tomosynthesis with low-dose MLO) [Group A]. 
 
3.2 
Secondary Aims 
3.2.1 To compare sensitivity of FFDM to the limited DBT set (digital breast two-view 
tomosynthesis with low-dose MLO) [Groups A and B]. 
 
3.2.2 To assess lesion-type characterization: 
3.2.2.1 To compare the sensitivity and specificity by lesion-type characterization 
(calcification-only lesions versus soft-tissue lesions, as well as lesion subgroups: 
masses, calcifications, architectural distortions, asymmetries) in FFDM versus 
DBT (two-view tomosynthesis set with low-dose MLO) [Group A call-back 
cohort and Group B]; 
3.2.2.2 To estimate the agreement of FFDM and DBT with the determination of the 
adjudication committee on lesion-type characterization. 
 
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3.2.3 To use the sequential interpretation results [Groups A and B] in order to compare the 
two-view limited tomosynthesis set (with low-dose MLO view alone) with the 
tomosynthesis plus set (low-dose MLO view plus addition of low-dose CC view) on the 
basis of: 
• Call-back rate; 
• Identification of  new lesion(s); 
• Lesion characterization; and 
• Triangulation.  
 
3.2.4 To calculate and compare the radiation dose of the FFDM and the DBT sets. 
 
3.2.5 To identify the determinants of participant radiation dose and clinical image quality, 
including factors such as kVp, mAs, target/filter combination, and breast thickness and 
composition. 
 
 
4.0 
STUDY OVERVIEW 
All participants will be consented and registered prior to their screening or diagnostic evaluation, which 
may be same day. If an eligible patient decides not to join the trial, her reason should be documented on 
a Screening Log to assist in identifying recruitment barriers. Participants will undergo both routine 
screening full field digital mammogram (FFDM) and the tomosynthesis imaging set (DBT) comprising: 
FFDM only (from screening in Groups A and B), as well as diagnostic imaging (FFDM, +/- ultrasound 
and other) when obtained on call-back in Group A and on all Group B patients; low-dose DBT—two-
view limited tomosynthesis set with low-dose 2-D MLO view (limited tomosynthesis set) and low-dose 
low-dose CC view (tomosynthesis plus set). However, the timing of the study-related imaging visits will 
be segregated into two cohorts, screening (Group A) and diagnostic (Group B). 
 
4.1  
Group A: Screening Tomosynthesis 
Group A comprises 500 asymptomatic women with no history of breast cancer who are scheduled for 
routine screening of the breasts with FFDM. The Group A component of the trial is powered to show a 
30% reduction in call-back rate from screening including DBT. Participants in Group A will undergo 
both FFDM and DBT. Initial interpretation from local readers will determine call back for diagnostic 
evaluation based on positive (abnormal) findings from either the conventional two-view digital 
mammography study—“FFDM only”—or the tomosynthesis imaging sets (limited tomosynthesis set 
and then a sequential read with the low-dose CC view added for the tomosynthesis plus set). Participants 
will be biopsied or followed as recommended by the physician who evaluated the participant at 
diagnostic call back. Local readers will be randomly assigned images to assess per institutional standard 
procedures and are blinded to the results of the complementary image set for the participant. Local 
readers also will be asked to assess image quality. Any necessary diagnostic evaluation from positive 
screening findings should be conducted within 30 days after screening visit. Follow up will include 
medical record review, review of conventional imaging results, and images collection at approximately 
1-year post-screening assessment. Follow-up data may be collected up to 18-months post-screening 
depending on participant’s scheduling; data may be collected over a shorter time period due to funding 
constraints. 
 
 
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4.2 
Group B: Diagnostic Tomosynthesis in an Enriched Population 
Approximately 50 asymptomatic women with no history of breast cancer who have been informed of 
positive (abnormal) findings from a recent (within 30 days) FFDM screening will be recruited to Group 
B prior to their diagnostic imaging (e.g., diagnostic FFDM and/or ultrasound and/or other). Group B 
participants will consent to DBT of both breasts as part of their diagnostic imaging work up; all 
screening and diagnostic images will be collected for study-related analysis. Participants will be 
biopsied or followed as recommended by the physician who evaluated the participant at diagnostic call 
back. Study-related follow up will include medical record review and images collection at 
approximately 1-year post-screening assessment. Follow-up data may be collected up to 18-months 
post-screening depending on participant’s scheduling; data may be collected over a shorter time period 
due to funding constraints. 
 
Enrollment to Group B will concentrate initially on calcification-only lesions (based on the report of the 
initial screening study), under the assumption that Group A will comprise predominantly soft-tissue 
lesions. Recruitment of call-back cases based on lesion type will be monitored to achieve 75%-to-50% 
soft-tissue lesions and 25%-to-50% calcification-only lesions within the enriched cohort. See Section 6.4 
for additional details.  
 
The enriched Group B population is designed to increase the number of true-positive and false-positive 
cases for comparison of the two imaging modalities at the lesion level. Images for lesion level analysis 
will comprise approximately 100 image-positive cases collected from both study cohorts (all of Group B 
and approximately 50 cases from Group A that result in call backs for diagnostic assessment). Analysis 
of the images performed at the lesion level will also assess the added contribution of the low-dose CC 
view when added to the two-view tomosynthesis plus low-dose MLO view image set. 
 
4.3 
ACRIN PA Trials and Hologic 
Potential participants will be recruited from Pennsylvania institutions with Hologic tomosynthesis units. 
While an important outstanding obstacle to routine use of tomosynthesis involves differences in 
technical parameters (radiation exposure in particular) used across competing scanner types, this study is 
limited to Pennsylvania-based sites only due to funding, and Hologic is the only manufacturer approved 
for use in Pennsylvania. The results of this trial are aimed at setting the stage for a larger screening trial 
where best-practices related to quality under specific technical parameters (radiation dose, image angle) 
across manufacturers might be better assessed.  
 
 
5.0 
PARTICIPANT SELECTION/ELIGIBILITY CRITERIA 
The trial’s study population comprises two cohorts: asymptomatic women ages 25 and older with no 
history of breast cancer 1) who are scheduled for screening mammography (Group A) or 2) who are 
recalled for additional diagnostic imaging based on image-positive findings from recent screening with 
FFDM (Group B). If an eligible patient decides not to join the trial, their reason should be documented 
on a Screening Log to assist in identifying recruitment barriers. 
 
5.1 
Inclusion Criteria 
5.1.1  Women 25 years of age or older; 
5.1.2 No history of breast cancer;  
5.1.3  Group A only: Asymptomatic and scheduled for screening mammography; 
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5.1.4  Group B only: Asymptomatic and recalled for diagnostic testing due to positive findings 
on recent screening using FFDM, completed within 30 days prior to registration  
(BI-RADS 0: additional imaging needed); 
5.1.5  Willing to provide a written informed consent. 
 
5.2 
Exclusion Criteria 
5.2.1  Pregnancy or intent to become pregnant; 
5.2.2  Unable or unwilling to tolerate compression associated with mammography; 
5.2.3  Breast implants; 
5.2.4 Breasts too large to allow for adequate positioning for the DBT examination; 
5.2.5  Group B only: Patients with FFDM taken at screening who are unwilling or unable to 
submit images to ACRIN; 
5.2.6  Group B only: Unwilling to undergo tomosynthesis on both breasts as well as potentially 
additional diagnostic imaging based on tomosynthesis findings; 
5.2.7 Unable or unwilling to complete screening and (as necessary) diagnostic imaging at same 
facility; 
5.2.8 Tomosynthesis or mammography within 11 months prior to registration. 
 
5.3 
Recruitment and Screening 
The research team at each participating site includes the radiologist principal investigator (PI), local 
radiologists for local reads in Group A, mammography and DBT technologists, and research 
associate(s). The local radiologists also will interpret the tomosynthesis image sets at the time of 
diagnostic imaging for Group B participants. The PI and other research staff will be responsible for the 
screening, review of participant medical records, and investigator-designated data submission. A total of 
3 to 4 readers at each site experienced in both digital mammography and tomosynthesis will be recruited 
to participate in this trial. 
 
5.4 
Inclusion of Women and Minorities  
The ACRIN-qualified participating institutions will not exclude potential participants from participating 
in this or any study solely based on ethnic origin or socioeconomic status. Every attempt will be made to 
enter all eligible participants into this protocol and therefore address the study objectives in a patient 
population representative of the entire English-speaking population at risk for breast cancer screened by 
the institution.  
 
Women of all ethnic groups are eligible for participation in this study. 
 
 
6.0 
SITE SELECTION 
6.1 
Institution Requirements 
The potential sites for this study are ACRIN-participating institutions in Pennsylvania that meet 
qualifications for participating in this study. Each institution must complete a Protocol Specific 
Application (PSA) (available online at www.acrin.org/4006_protocol.aspx) and undergo ACRIN-
qualification for digital mammography and tomography equipment and software to be used for the trial 
prior to the institution participating in the study (Appendix II).  
ACRIN PA 4006 
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Detailed information for Digital Mammography and Tomography Qualification Procedures and the 
application to become ACRIN qualified, as well as the PSA, can be accessed at 
www.acrin.org/4006_protocol.aspx. All qualification documentation must be submitted to ACRIN 
Headquarters for review and approval. 
 
6.2 
Local Reader Qualifications 
6.2.1 All digital mammogram and tomosynthesis readers must be accredited under the 
Mammography Quality Standards ACT (MQSA) and have tomosynthesis experience 
(defined as 30 previous reads or more). 
 
6.3 
IRB Approval and Informed Consent Form 
The study will be approved by the appropriate institutional review boards (IRBs) and the appropriate 
institutional review committees. All study participants will provide written informed consent (see the 
Informed Consent Form Template in Appendix I). 
 
All institutions must have site-specific, initial full-board IRB approval for the protocol and informed 
consent form (ICF) for this study. (A sample ICF is included in this protocol as Appendix I and may be 
adjusted for local IRB submission.) The investigator and the investigator-designated research staff must 
follow OHRP-approved consent procedures (Title 45, Part 46 Code of Federal Regulations), as well as 
those set by the local IRB at the institution. A copy of the IRB approval letter, a copy of the IRB-
approved, site-specific ICF, evidence of completion of the OHRP Human Subjects Assurance Training 
(or institution-specific equivalent), and FDA Form 1572 Statement of Investigator and CVs and medical 
licensure for all research staff listed in Form 1572 must be submitted to the ACRIN study monitor for 
review and to keep on file at ACRIN Headquarters (fax: 215-717-0936, ATTN: ACRIN PA 4006 Study 
Monitor) prior to registering the first participant. 
 
6.4  
Accrual Goals and Monitoring 
The ACRIN Biostatistics and Data Management Center (BDMC) will monitor participant accrual. Total 
target accrual for this study is 550 participants. During the first year, the accrual goal will be 550 
participants. If the target is not reached, a review will be conducted with the intention of discovering and 
resolving any recruitment barriers. 
 
Accrual and safety information will be presented to the ACRIN PA (Pennsylvania) Data and Safety 
Monitoring Board (DSMB) at regularly scheduled meetings thereof; the PA DSMB may, at its 
discretion, re-evaluate the study with respect to feasibility or the need for additional participating 
institutions. 
 
In Groups A and B, monitoring of lesion type will be necessary to ensure inclusion of an appropriate 
number of calcification-only lesions for meaningful assessment by lesion type. Under the assumption 
that the majority of cases called back from Group A screening FFDM and tomosynthesis will be soft-
tissue lesions, the trial will focus on recruiting participants to Group B who are called back for 
diagnostic work-up based on calcification-only lesions seen on screening FFDM. Recruitment of call-
back cases based on lesion type will be monitored throughout the study. Group B will not be closed to 
accrual of soft-tissue cases during the trial, but recruitment will focus on calcification-only lesions. 
ACRIN PA 4006 
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June 14, 2010 
 
 

 
Based on ACRIN 6652 DMIST data, the target accrual by lesion type is 75%-to-50% soft-tissue lesions 
to 25%-to-50% calcification-only lesions.  
 
 
7.0 
DATA MANAGEMENT/ONLINE REGISTRATION  
7.1 
General 
7.1.1 
The ACRIN web address is www.acrin.org. 
 
7.1.2 
Data collection and management will be performed by the Biostatistics and Data 
Management Center (BDMC) of ACRIN under the direction of Dr. Constantine 
Gatsonis. The Biostatistics Center (BC) is located at Center for Statistical Sciences at 
Brown University in Providence, RI, and the Data Management Center (DMC) is 
located at ACRIN in Philadelphia, PA. 
 
7.1.3 
Participant enrollment and data collection occurs through a series of programmed 
screens accessed through the ACRIN web site to register/randomize participants, 
collect participant data, and maintain calendars of data submissions for each 
participant. By using the World Wide Web, ACRIN has made participant registration, 
data entry, and updated calendar information available to clinical sites 24 hours a day, 
seven days a week. Each successful case registration is confirmed through receipt of an 
e-mail containing a registration/randomization confirmation and a case specific 
calendar identifying timelines for data and image submission. If the confirmation e-
mail is not received, the enrolling person should contact the DMC before attempting a 
re-registration. A DMC contact list is located on the ACRIN web site for each protocol. 
 
7.2 
Clinical Data Submission 
7.2.1 
Upon successful participant registration to Group A (screening) or Group B 
(diagnostic), a confirmation e-mail containing the registration and case specific 
calendar is sent to the research staff enrolling the participant via the web. In addition, 
the investigator-designated research staff may download the participant specific data 
submission calendar, which lists all forms and designated reports required by protocol, 
along with the form due dates at the DMC. These calendars will be updated as the study 
proceeds to reflect data that have been received, reply deadlines for queries about 
unclear data, deadlines for follow-up reports of adverse events, or changes in the 
protocol that change the data being collected or the timeframe. Updated calendars for 
each participant can be obtained 24 hours a day from the ACRIN web site. The research 
associate may use the calendar as a case management tool for data submission and 
follow-up scheduling.  
 
7.2.2 
The investigative site is required to submit data according to protocol as detailed on 
each participant’s calendar, as long as the case status is designated as open/alive or 
until the study is terminated. The case is closed when all data have been received, 
reviewed, and no outstanding data query exists for the case. 
 
7.2.3 
To submit data via the ACRIN web site, the appropriate investigator-designated 
research staff will log onto the ACRIN web site and supply the pre-assigned user name 
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and password. Case report forms will be available on the web site through a series of 
links. Each web form is separated into modules; each module must be completed 
sequentially in order for the internal programming to be accurate. The user selects the 
link to the appropriate form and enters data directly into the web-based form. As 
information is entered into the web form application, various logic checks will be 
performed. These logic checks look for data that are missing, data that are out of range, 
and data that are in the wrong format (e.g. character data in a field requiring numeric 
responses). Such errors will be detected as soon as the user attempts to either submit the 
form or move to the next data element. They must be corrected before the form is 
transmitted to the DMC. The user will not be able to finalize form transmission to the 
DMC until all data entered pass these logic checks. Forms that are not completed in one 
sitting can still be submitted and completed at a later date. The form will remain 
available on the web until the “Complete Form Submission” button is depressed.  
 
7.2.4 
Once data entry of a form is complete, and the summary form is reviewed for 
completeness and accuracy, the investigator or the research staff presses the “Complete 
Form Submission” button on the form summary screen and the data are transferred into 
the clinical database. No further direct revision of the submitted data is allowed after 
this point. E-mail confirmation of web data entry is automatically generated and sent to 
the site investigator or research associate listing all of the data generated and just 
submitted. Should a problem occur during transmission and the e-mail confirmation of 
data submission is not received, the investigator or research associate should contact 
the DMC for resolution of the submission. 
 
7.2.5 
If a temporary problem prevents access to the Internet, all sites are notified of the event 
and estimated down time through an ACRIN broadcast message. The investigative site 
should wait until access is restored to submit data. The site research associate or 
investigator should notify the DMC of the problem and the DMC will give an estimated 
time when access will be restored. If access will be unavailable for an extended period, 
sites must seek another Internet Service Provider (ISP). On a short-term basis, ACRIN 
can serve as an ISP. 
 
7.3 
Registration Protocol 
Once the patient has been found to be eligible to participate in the trial, the potential participant will be 
consented (see Informed Consent Form Template in Appendix I). Upon obtaining a signed ICF, the 
research staff will register the participant by logging onto the ACRIN web site (www.acrin.org), and 
selecting the link for Data Center Login.  
 
The registration screen begins by asking for the date on which the eligibility review was completed, 
identification of the person who completed the review, whether the potential participant was found to be 
eligible on the basis of the review, and the date the study-specific informed consent form was signed. 
 
After completing the registration, the system assigns a participant-specific case number. The system 
then moves to a screen, which confirms that the participant has been successfully enrolled. This screen 
can be printed so that the registering site will have a copy of the registration for the participant’s record. 
 
ACRIN PA 4006 
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June 14, 2010 
 
 

 
Participants will be identified according to their study group assignments (Group A—screening—or 
Group B—diagnostic). 
 
7.3.1 Unsuccessful Registrations 
Any problems or questions regarding registration of participants should be directed to the 
ACRIN DMC. Never re-register a participant as this may lead to duplicate case numbers.  
 
7.4 
Data Security 
The registration and data collection system has a built-in security feature that encrypts all data for 
transmission in both directions, preventing unauthorized access to confidential participant information. 
Access to the system will be controlled by a sequence of identification codes and passwords. 
 
7.5 
Electronic Data Management 
7.5.1 
Data received from the web-based forms are electronically stamped with the date and 
time of receipt by the ACRIN server. The data are then entered into the database. A 
protocol-specific validation program is used to perform more extensive data checks for 
accuracy and completeness. Complementary validation programs are initiated at the 
Brown BC and the ACRIN DMC. The logic checks performed on the data at this point 
are more comprehensive than those built into the web-based data entry screens. They 
include checking that answers are logical, based on data entered earlier in the current 
form and the more thorough checks. Data elements that fail validation are followed up 
by the DMC. The validation program generated by BC produces a log of errors, which 
is sent to the DMC for resolution. The program is frequently updated to incorporate 
exceptions to rules so that subsequent validity checks minimize the time the DMC 
needs to spend resolving problems. Additional data review will take place once the data 
are transferred to the BC. The BC will run thorough cross-form validations, frequency 
distributions to look for unexpected patterns in data, and other summaries needed for 
study monitoring. Any errors found at the BC will be reported to the DMC for 
resolution. All BDMC communication with the participating sites is normally done 
through the DMC.  
 
7.5.2 
If checks at DMC or BC detect missing or problematic data, the DMC personnel 
assigned to the protocol sends a Request for Information (Z1 query letter) to the site 
research associate or investigator specifying the problem and requesting clarification. 
The DMC updates the participant’s data submission calendar with the due date for the 
site research associate or investigator’s response. 
 
7.6 
Missing and Delinquent Data Submission 
In addition to providing the investigator a data collection calendar for each case, the DMC periodically 
prompts institutions for timely submission of data through the use of a Forms Due Report. Distributed at 
intervals via the electronic mail system directly to both the research associate and the investigator at 
each site, this report lists data items (e.g. forms, reports, and images) that are delinquent and those that 
will be due before the next report date. In addition to prompting clinicians to submit overdue data, the 
Forms Due Report helps to reconcile the DMC’s case file with that of the research associate and/or 
investigator. Future Due Forms Reports may be sent on an as needed basis in addition to past due 
ACRIN PA 4006 
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reports. The site investigator or research associate may use the Forms Due and Future Due Reports as a 
case management tool. 
 
7.7 
Data Quality Assurance  
7.7.1 
The BC at Brown University will maintain a study database at its site for monitoring 
data quality and for performing analyses. These data are drawn directly from the 
permanent database of the DMC. The transfer of data between the DMC and the BC 
has been validated through a series of checks consisting of roundtrip data verification in 
which data are sent back and forth to verify that the sent data are equivalent to the 
received data. These checks are repeated at random intervals during the course of a 
given study. Any discrepancies and other data quality issues will be referred to DMC 
for resolution, since only the DMC can correct the data file. No changes to the data 
will be made at the BC.  
 
7.7.2 
A goal of the monitoring of data is to assess compliance with the protocol and to look 
for unforeseen trends that may be indicative of procedural differences among clinical 
sites. If patterns are discovered in the data that appear to arise from causes specific to 
an institution, the BDMC will apprise the ACRIN Headquarters and the site of the 
problem, and work with the site, along with ACRIN Protocol Development and 
Regulatory Compliance (PDRC) department, until the problem has been resolved. If the 
BDMC, along with the PDRC, cannot find a resolution to the problem, it will be 
brought to the ACRIN Quality Assurance (QA) Committee for further discussion and 
resolution.  
 
 
8.0 
STUDY PROCEDURES 
8.1 
PRIOR TO IMAGING: Eligibility & Registration  
8.1.1 Obtain a signed informed consent form; 
8.1.2 Baseline assessment to determine eligibility based on details in Section 5.0 will comprise 
the following: 
• Obtain medical history including: 
o Demographic risk assessment form; 
• Obtain pregnancy test, if woman is of childbearing potential, per institutional 
standard of care; 
8.1.3 Collect contact information for participant and proxy for site staff to make telephone 
contact only in the event that approximate 1-yr follow up medical record extraction and 
images collection is unavailable from known treating physician; 
8.1.4 Register the eligible participant to Group A (screening) or Group B (diagnostic); 
8.1.5 Screening or diagnostic imaging should occur same day as scheduled previously (unless 
the potential participant requests additional time to consider joining the trial, in which 
case delays in rescheduling should be minimized). 
 
NOTE: If an otherwise eligible patient decides not to join the trial, their reason should be 
documented on a Screening Log to assist in identifying recruitment barriers. 
ACRIN PA 4006 
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June 14, 2010 
 
 

 
. 
8.2 
Group A Only Procedures 
8.2.1 GROUP A IMAGING: Screening (FFDM with DBT) 
Participants enrolled to Group A, a cohort of asymptomatic women ages 25 and older 
with no history of breast cancer and no implants, will undergo the following procedures 
during routine breast cancer screening: 
• Confirm/collect current participant and proxy contact information; 
• FFDM per institutional standard of care; 
• Study-related tomosynthesis imaging sets (limited and tomosynthesis plus sets) 
according to parameters provided in the ACRIN PA 4006 Imaging Manual (available 
at www.acrin.org/4006_imagingmaterials.aspx); 
• Assessment for AEs. 
 
8.2.2 Local Reader Clinical Assessment 
Local radiologists (see Section 6.2 for qualifications) will be responsible for the clinical 
read of screening FFDM and DBT under the following restrictions: 
• Site PI will randomly assign images to local readers; 
• Readers will be blinded to the complementary imaging for a participant (i.e., no local 
radiologist will read both FFDM and DBT for an individual); 
• Images will be assessed for clinical significance, lesion(s) location and type (broadly 
as soft-tissue or calcification-only lesions for monitoring purposes, as well as 
subgroup analysis of mass, asymmetry, architectural distortion and calcifications), 
and quality; 
• Image-positive results from either FFDM or DBT, or both, will require call back for 
diagnostic imaging follow up (BI-RADS = 0, additional imaging needed). 
 
8.2.3 Diagnostic Imaging (Positive Screening Results Only) Within 30 Days After 
Screening 
• Follow-up diagnostic imaging and possible biopsies will be per institutional standard 
of care (diagnostic FFDM, ultrasound, and/or other procedures); 
• Follow-up diagnostic imaging must be completed within 30 days after screening 
imaging is completed; 
• Further evaluation or follow-up procedures will be conducted per institutional 
standard of care; 
• Results of diagnostic assessment and follow up will be submitted to ACRIN. 
 
8.3 
Group B Only Procedures 
8.3.1 Pre-Trial Screening: Collection of Images 
The initial screening study from which the call-back recommendation was generated 
must have been completed within 30 days prior to the call-back diagnostic imaging visit. 
The initial screening FFDM that led to the patient call back will need to be submitted to 
ACRIN for study-related assessment. 
 
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June 14, 2010 
 
 

 
8.3.2 GROUP B IMAGING: Call-Back Diagnostic Imaging (Standard-of-Care Imaging, 
Including FFDM, and DBT) Within 30 Days After Screening 
Participants enrolled to Group B, a cohort of asymptomatic women ages 25 and older 
with no history of breast cancer and no implants who have had image-positive screening 
results (abnormal findings, BI-RADS = 0, additional imaging needed), will undergo the 
following procedures on both breasts during routine call-back diagnostic imaging: 
• Diagnostic FFDM and/or ultrasound (and any other standard imaging and procedures) 
per institutional standard of care; 
• Confirm/collect current participant and proxy contact information; 
• Study-related tomosynthesis imaging sets (limited and tomosynthesis plus sets) 
according to parameters provided in the ACRIN PA 4006 Imaging Manual (available 
at www.acrin.org/4006_imagingmaterials.aspx); 
• Assessment for AEs.  
 
8.3.3 Local Reader Clinical Assessment: Sequential Reads 
Local radiologists (see Section 6.2 for qualifications) will be responsible for the clinical 
read of diagnostic imaging under the following restrictions: 
• Diagnostic images will be read sequentially: 
1. FFDM (screening and diagnostic; historical patient imaging will be 
available per institutional standard of care); 
2. Two-view limited tomosynthesis image set with low-dose MLO view 
only;  
3. Two-view tomosynthesis plus image set with low-dose MLO and addition 
of low-dose CC view; 
4. Any other standard imaging and procedures (e.g., ultrasound). 
• Images will be assessed for clinical significance, lesion(s) location and type (broadly 
as soft-tissue or calcification-only lesions, as well as subgroup analysis of mass, 
asymmetry, architectural distortion and calcifications), and quality; 
• Further evaluation or follow up procedures will be conducted per institutional 
standard of care. 
 
8.4 
GROUPS A and B FOLLOW UP: Medical Records Review and Images Collection at 
Approximately One (1) Year Post-Screening 
8.4.1 Follow-Up Responsibilities 
Sites will be responsible for follow-up data collection at approximately one (1) year post-
screening for Groups A and B. Study-related follow up may be necessary up to 18 
months post-screening depending on participant accessibility and clinical follow-up 
scheduling. Study-related follow up may be truncated due to funding and related trial-
completion limitations. 
8.4.2 Follow-Up Procedures 
• Participant  status will be determined at approximately one (1) year post-screening;  
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AC
 
RIN PA 4006 
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June 14, 2010
 
• All participant data from image-positive call-back cases and interval cancers will be 
reviewed in adjudication to classify them as calcification-only or soft-tissue lesions 
(further delineated by subtype—e.g., mass, asymmetry, architectural distortion); this 
classification will serve as basis for comparison with local reader results (see Sections 
9.3 and 15.5).  
• A Follow-Up Manual detailing the specifics of contact and other procedures is 
available at www.acrin.org/4006_imagingmaterials.aspx 
• If treating physician is no longer overseeing participant care, telephone contact will 
be made with the participant or proxy to facilitate contact with new treating physician 
or to determine current breast cancer-related status at minimum;  
• Research staff will contact the participant’s treating physician for medical records 
extraction and to assist in submission of follow-up images to ACRIN; 
 

 
ACRIN PA 4006 
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June 14, 2010 
 
8.5 
Study Procedures Table 
FFDM, full-field digital mammography. 
* The screening FFDM that prompted the recommendation for call back for potential Group B participants will have to be available for submission to ACRIN for patients 
to qualify for participation in the Group B arm.
GROUP A (SCREENING)  
 
(30 Days Between Screening and Diagnostics) 
GROUP B (DIAGNOSTIC) 
 
(30 Days Between Screening and Diagnostics) 
 
 
 
 
Study Procedures 
 
 
 
PRIOR TO 
IMAGING: 
Eligibility and 
Registration 
(BOTH 
GROUPS) 
IMAGING: 
Screening  
Local 
Reader 
Clinical 
Assessment 
Positive 
Screening 
Cases: 
Diagnostic 
Assessment 
Pre-Trial 
Screening* 
IMAGING: 
Diagnostic 
Imaging 
Local 
Reader 
Sequential 
Clinical 
Read 
 
 
FOLLOW UP: 
Approximately 
One (1) Year  
Post-Screening 
(BOTH 
GROUPS) 
Informed Consent Form 
X 
 
 
 
 
 
 
 
Eligibility/Registration 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Collect/Confirm Participant 
and Proxy Telephone 
Contact Information 
X 
X 
 
 
 
X 
 
 
Pregnancy Test for Women 
of Childbearing Potential 
X 
 
 
 
 
 
 
 
Standard Screening FFDM 
 
X 
 
 
X* 
 
 
 
Tomosynthesis Image Sets 
(see Section 9.0) 
 
X 
 
 
 
X 
 
 
Standard Diagnostic FFDM 
and/or Ultrasound 
 
 
 
X 
 
X 
 
 
Local Clinical Images Read 
 
 
X 
X 
X 
 
X 
 
Images Submission to 
ACRIN 
 
X 
 
X 
X* 
X 
 
X 
Reader Results Submission 
to ACRIN 
 
 
X 
X 
X 
 
X 
X 
Assessment for AEs 
 
X 
 
 
 
X 
 
 
Medical Records Extraction 
 
 
 
 
 
 
 
X 
Contact with Treating 
Physician and/or Participant 
and/or Proxy 
 
 
 
 
MONITORING (BY LESION TYPE)
 
MONITORING (BY LESION TYPE)
 
 
X 

 
9.0  IMAGING AND READER STUDIES PROTOCOLS  
9.1 
Imaging Parameters 
Imaging parameters for the tomosynthesis sets have been developed in accordance with Hologic’s 
guidelines and the overall strategy of maintaining the tomosynthesis dose at approximately 1.2 mGy and 
the low-dose FFDM dose at approximately 1.0 mGy for a 5.0-cm thick breast in the combined 
tomosynthesis+FFDM acquisition. The thickness-dependent doses are to be posted online at 
www.acrin.org/4006_imagingmaterials.aspx. 
 
Monitoring of radiation dose will be a part of the image quality assurance program for this trial, and 
sites with higher average doses will be given feedback by the core lab and PI concerning methods to 
reduce dose. 
 
9.2 
Images Submission 
The protocol-required images must be in DICOM format on CD/DVD-ROM or submitted via the 
Internet using the TRIAD transfer system, which facilitates DICOM exchange processes. ACRIN can 
provide TRAID software for electronic image submission and anonymization to participating 
institutions.  Images should be transmitted along with an Imaging Transmittal Worksheet (ITW) that can 
be found on the ACRIN PA 4006 web site at: www.acrin.org/4006_imagingmaterials.aspx. The required 
images must be submitted to the ACRIN core laboratory. Prompt submission of all image data is 
essential to ensure adequate quality control. For support in sending the images via the Internet using 
TRIAD, contact the representatives of the core lab via email at Triad-Support@phila.acr.org or via 
phone: 215-940-8820. 
 
Instructions for image submission and anonymization, as well as information regarding Quality Control, 
are available at: www.acrin.org/4006_imagingmaterials.aspx. 
 
9.3 
Local Reads and Adjudication of Cases 
9.3.1 Local Reader Assessments 
For screening Group A, local reads will comprise quality and diagnostic assessments of 
the image sets—2-D FFDM and the tomosynthesis image sets. Two radiologists 
minimum at each site will be needed for the study; images will be randomly assigned by 
the site PI; and local readers will be blinded to the other radiologists’ interpretation of the 
complementary images. Positive findings on either FFDM or tomosynthesis reads will be 
defined as “image positive” cases and lead to call-back for diagnostic assessment. 
 
For diagnostic Group B, local reads will comprise successive reads of 1) screening and 
diagnostic FFDM images followed by 2) the limited tomosynthesis set (with low-dose 
MLO view only) followed by 3) the tomosynthesis plus set (low-dose MLO view with 
the addition of low-dose CC view). Finally, any additional diagnostic assessment (e.g., 
ultrasound) will be read. Positive (abnormal) findings from the tomosynthesis imaging 
sets may lead to additional diagnostic procedures for participants. 
 
9.3.2 Adjudication of Cases Using All Participant Data 
Further assessment of images will focus on lesion subtypes. Distinctions in lesion 
identification, characterization, and triangulation across imaging platforms will be made 
after adjudication of cases by Drs. Copit and Conant (see Section 15.5). This will allow 
comparison of call-back rates and sensitivities by lesion type across the image sets 
(FFDM versus limited tomosynthesis image set versus tomosynthesis plus image set, 
ACRIN PA 4006 
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June 14, 2010 
 

 
which includes the low-dose CC view). Data from all interval cancers diagnosed during 
the follow-up period (up to 18 months after screening) will be adjudicated, as well. 
 
9.4 
Assessment of Tomosynthesis-Imaging Parameters  
9.4.1 Radiation Exposure and Quality 
Analysis will compare combinations of tomosynthesis sets on all cases to allow a cap of 
approximately 3.4 mGy of radiation exposure per breast on average. The 3.4 mGy 
exposure would be equivalent to the national average for two-view mammography 
radiation exposure. Additional assessments will allow for subsequent analyses of image 
quality and specificity as compared with the adjudication results (see Section 15.5).  
 
In this evaluation, 500 image sets from Group A will be used to compare two-view 
FFDM with the tomosynthesis image sets in the following combinations: 
• FFDM only (average dose per average breast = approximately 3.4 mGy). 
• Two-view limited tomosynthesis image set with low-dose MLO view only (low-dose 
2-D MLO and two-view DBT average dose = approximately 3.4 mGy). 
• Two-view tomosynthesis plus image set with low-dose MLO and addition of low-
dose CC view (low-dose projection CC and MLO plus two-view DBT average dose = 
approximately 4.4 mGy). FFDM plus all diagnostic mammographic imaging at call-
back versus the tomosynthesis image sets. The approximate dose per breast for two-
view, 2-D mammography is 3.4 mGy. The dose for the complete DBT (two-view 
tomosynthesis at approximately 1.2 mGy each, plus two simultaneously acquired 
low-dose 2-D CC and MLO views at 1.0 mGy each) is approximately 4.4 mGy which 
is comparable to conventional mammography.   
 
9.4.2 Quality and Lesion Subtypes 
In addition to comparison between imaging modalities, quality of images (including 
spatial completeness, linear and feature sharpness, etc) will be assessed based on local 
reader and adjudication assessments for lesion subtypes. 
 
 
10.0 
ADVERSE EVENTS REPORTING 
10.1 
Definition of Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence in a participant that does not necessarily 
have a causal relationship with the study intervention. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory or physiological finding), symptom, or disease 
temporally associated with the use of a medical treatment or procedure, regardless of whether it is 
considered related to the medical treatment or procedure (attribution of unrelated, unlikely, possible, 
probable, or definite). Abnormal results of diagnostic procedures are considered to be AEs if the 
abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event (SAE) 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
10.2 
Definition of Serious Adverse Event 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that:  
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• results in death, or 
• is life-threatening (at the time of the event), or  
• requires inpatient hospitalization or prolongation of an existing hospitalization, or 
• results in persistent or significant disability or incapacity, or  
• is a congenital anomaly/birth defect. 
 
10.3 
Adverse Event Grading 
Grade denotes the severity of the AE. An AE is graded using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0:  
 
 
 
 
1 – Mild  
 
 
 
2 – Moderate 
 
 
 
3 – Severe 
 
 
 
4 – Life-threatening or disabling 
 
 
 
5 – Fatal 
 
A copy of the CTCAE can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
10.4 
Adverse Event Attribution 
Attribution determines whether an AE is related to a study treatment or procedure. Attribution 
categories are: 
Definite  – AE is clearly related to the study treatment or procedure. 
Probable – AE is likely related to the study treatment or procedure. 
Possible  – AE may be related to the study treatment or procedure. 
Unlikely –  AE is doubtfully related to the study treatment or procedure. 
Unrelated – AE is clearly NOT related to the study treatment or procedure. 
 
10.5 
Potential Expected and Unexpected Adverse Events 
AEs may be expected or unexpected:  
• An expected AE is one that is described in the protocol, the ICF, or the investigator’s 
clinical brochure.  
• An unexpected AE is one that has not been described in the protocol, the ICF, or the 
investigator’s clinical brochure. 
 
10.6  Expected Adverse Event(s) for Study Procedures (Groups A and B) 
Only AEs with grades 3, 4, and 5 that are considered possibly, probably, or definitely related to 
the study-related tomosynthesis scan procedures require reporting to ACRIN. Please refer to 
your local IRB’s policies regarding AEs. 
 
10.6.1 Expected Adverse Events From Tomosynthesis 
Likely 
• Discomfort from breast compression that is similar to routine mammography; 
• Bruising similar to routine mammography. 
 
10.6.2 Expected Adverse Events Associated With Radiation Exposure  
 
From Tomosynthesis 
The radiation dose from a tomosynthesis study of the breast varies depending upon 
patient size, scanner used, technique used, and the use of available methods for dose 
ACRIN PA 4006 
24 
June 14, 2010 
 
 

 
reduction. The radiation dose will be matched to the breast size per the manufacturer’s 
specifications, optimizing the dose for each participant.  
 
Utilizing these techniques, the radiation dose associated with this tomosynthesis protocol 
will be an average of 4.4 mGy for a breast of 5.0-cm thickness. By comparison, the 
national average dose for mammography is approximately 3.4 mGy for the same breast 
size. Thus, the radiation risk from this study is little different from that of a standard 
mammogram.  
 
The radiation dose of the study images doubles the participant’s radiation exposure since 
the participant will undergo both mammography and tomosynthesis. However, the 
combined exposure is many orders of magnitude less than that associated with 
deterministic effects. Thus, no deterministic effects are anticipated. 
 
Stochastic radiation effects can be estimated from the effective dose. The effective dose 
from the study images is 0.22 mSv assuming a tissue weighting factor (wT) of 0.05.10 By 
comparison, the national average ubiquitous background radiation is 3.1 mSv,11 and more 
than 2.3 million people in the United States are exposed to more than 20 mSv per year 
without known detriment. For the purposes of radiation safety, a linear no-threshold 
model is assumed for solid cancer incidence. Based on this model, the current estimate of 
the lifetime risk of a fatal solid cancer is 0.05 per Sv (for the general public) or 
approximately 1.1x10-5 (1.1 in 100,000) for the study images. 
 
10.7 
Recording of Adverse Events 
Prompt reporting of AEs is the responsibility of each investigator, clinical research associate (RA), 
and/or nurse engaged in clinical research. Please refer to Table A below and Sections 10.8 and 10.9 for 
specific details about reporting. Anyone uncertain about whether a particular AE should be reported 
should contact ACRIN headquarters at 215-574-3183 for assistance. However, an AE report should be 
submitted if there is a reasonable suspicion that the AE may be related to the study procedures. 
   
Routine reporting is defined as documentation of AEs on source documents and the AE case report 
form (CRF), and submission to ACRIN for preparation of a report for DSMB review, and the final study 
report. 
 
Expedited reporting is defined as immediate notification of ACRIN within the specified timeframe 
outlined in the protocol and in Table A below.  Routine reporting requirements also apply. 
ACRIN PA 4006 
25 
June 14, 2010 
 
 

 
TABLE A  
Reporting Requirements for AEs occurring within 30 Days of the last use of a study-related device1 
 
Grade 1 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
Grade 5 
Unexpected 
Unexpected 
Expected 
 
Unexpected  
and Expected 
with 
Hospital-
ization 
without 
Hospital-
ization 
 
 
Expected 
with  
Hospital- 
ization 
without 
Hospital- 
ization 
with  
Hospital- 
ization 
without 
Hospital- 
ization 
Unex-
pected  
Expected 
 
Unexpected 
 
 
Expected 
 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required  
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
10 
10 
10 
Calendar 
Not 
Calendar 
Calendar 
Required 
Days 
Days 
Days 
Possible 
Probable 
Definite 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
10 Calendar
Days 
10 Calendar
Days 
Not 
Required 
Not 
24-Hour; 
24-Hour; 
5 
Calendar 
Days 
10 
Calendar 
10 
5 Calendar 
Calendar 
Required 
Days 
Days 
Days 
 
Hospitalization is defined as initial hospitalization or prolongation of hospitalization for ≥ 24 hours, due to adverse event. 
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to agent administration or other cause must be provided. 
 
1 
Adverse events that occur more than 30 days after the last exposure to the investigational device and have an attribution of possible, probable, or definite 
require reporting as follows: 
 
24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 Unexpected Events 
 
10 calendar day report: 
• 
Grade 3 Unexpected Events with or without Hospitalization 
• 
Grade 4 Expected Events 
• 
Grade 5 Expected Events 
 
 
At each contact (site visit and/or telephone) with the study participant, the investigator or investigator-
designee must seek information on AEs through discussion and, as appropriate, by examination. 
Information on expected and unexpected AEs considered possibly, probably, and/or definitely related 
to the study components of the ACRIN PA 4006 trial with grades of 3, 4, or 5 should be recorded 
immediately into the source document (e.g. AE Log and/or progress notes of the study participant’s 
chart) and retained at the site.  
 
Study related AEs must be recorded in the AE CRF and reviewed by the principal site investigator in 
real time to determine grade and attribution of the event. If the AE meets the criteria for serious and 
requires expedited reporting, an ACRIN SAE Report will be completed (refer to Section 10.9 for 
detailed instructions).  
 
AEs already documented in an AE CRF (i.e., at a previous assessment) and designated as ‘ongoing,’ 
should be reviewed at subsequent visits as necessary. If these have resolved, the documentation in the 
AE CRF should be completed including an end date for the event and not the date of the visit. If an 
adverse experience increases in frequency or severity during a study period, an up-to-date record of the 
experience will be documented. Each AE should be followed until resolution, stabilization, or until it has 
been determined that the study procedure or study participation is not the cause. Any SAE that occurs 
after the study period and is considered to be possibly related to the study procedures or study 
participation should be recorded and reported immediately. 
ACRIN PA 4006 
26 
June 14, 2010 
 
 

 
 
 
10.8 
When to Report 
It is the responsibility of the investigator to document all AEs (as identified in Section 10.6) that occur 
during the course of the study including any unexpected AEs with grades 3, 4, and 5 with attributions of 
possible, probable, and definite. At each designated visit, the investigator will evaluate for any AEs. 
AEs not previously documented in the study will be recorded within the study participant’s chart to 
identify any AEs potentially related to any study procedures. The nature of each event, date and time 
(when appropriate) of onset, outcome, frequency, maximum intensity, action taken, and attribution will 
be recorded.  
 
10.8.1 When to Report 
You must use the following AE reporting criteria for all protocol-specific AEs/SAEs:  
   
1. 
Grade 3 unexpected AEs with hospitalization that are possible, probable, or 
definite require a complete SAE report to be submitted within 10 calendar 
days of first knowledge of the event. Routine reporting procedures also 
apply.  
2. 
Grade 3 expected AEs with hospitalization that are possible, probable, or 
definite will be reported by routine reporting procedures only. 
3. 
Grade 3 unexpected and expected AEs without hospitalization that are 
possible, probable, or definite will be reported by routine reporting 
procedures only. 
4. 
Grade 4 or 5 expected AEs that are possible, probable, or definite require a 
complete SAE report to be submitted within 10 calendar days of first 
knowledge of the event. Routine reporting procedures also apply. 
5. 
Grade 4 or 5 unexpected AEs that are possible, probable, or definite will be 
reported via phone report within a 24-hour time period to ACRIN by the 
investigator or investigator-designee. In addition, a complete SAE report is 
due within 5 calendar days of the initial 24-hour telephone report. Routine 
reporting procedures also apply. 
6. 
Expedited AE reporting must be completed within 5 to 10 working days of 
first knowledge of the event according to the descriptions above.   
 
10.8.2  Assignment of grades and attribution for each AE/SAE must be completed by the site 
principal investigator. All AEs/SAEs should be documented in the study participant’s 
chart and CRFs. For expedited SAE reports, a copy of the report must be kept at the site. 
Significant new information on any on-going SAE should be promptly reported to 
ACRIN.  
 
10.9 
How to Report 
10.9.1 An expedited AE report requires submission to ACRIN using the ACRIN SAE Report.   
 
10.9.2 Completed expedited reports should be sent to: 
 
 
 
Lia Worley, ACRIN AE Coordinator 
 
 
  
Re: Serious Adverse Event Report 
 
 
 
ACRIN PA 4006  
 
 
 
1818 Market Street, 16th Floor 
ACRIN PA 4006 
27 
June 14, 2010 
 
 

 
 
 
 
Philadelphia, PA  19103 
 
10.9.3 A copy of all SAE reports should be sent to ACRIN by fax at (215) 940-8819. All deaths 
should be reported by telephone within 24-hours of first knowledge of the event. To 
make a telephone report to ACRIN, call (215) 717-2763, available 24 hours a day 
(recorder available Monday through Friday from 4:30 PM to 8:00 AM Eastern Time and 
on weekends). 
 
10.9.4 All expedited AE reports should be sent to your local Institutional Review Board (IRB).  
Please refer to your local IRB’s policies regarding AEs.   
 
 
11.0 
ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical Practice 
(International Conference of Harmonisation [ICH] guidelines), applicable government regulations, and 
ACRIN research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Institutional 
Review Board (IRB) for formal approval of the study conduct. The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator and a copy of this decision will be 
provided to ACRIN before implementation of the study.  
 
The investigator will provide ACRIN with the institution’s federal wide assurance (FWA) number, 
along with the IRB approval letter and copy of the IRB-approved informed consent form (ICF). The 
investigator will provide a copy(s) of IRB approval letter(s) for any amendment(s), and copy(s) of 
annual renewal(s). 
 
All study participants in this study will be given an IRB-approved, site-specific ICF describing the study 
and providing sufficient information for participants to make informed decisions about their 
participation in this study (see Appendix I for an ICF template). The ICF will be submitted along with 
the protocol for review and approval by the local IRB. The study participant MUST be consented with 
the EC/IRB-approved ICF before the participant is subjected to any study procedures. The IRB-
approved ICF MUST be signed and dated by the study participant or legally acceptable representative 
and the investigator-designated research staff obtaining the consent before the participant is subjected to 
any study procedures. Any revisions to the ICF at any time during the trial will need to be submitted to 
the IRB for approval, followed by submission to ACRIN PDRC.  
 
 
12.0 
CONFLICT OF INTEREST 
Any investigator and/or research staff member who has a conflict of interest with this study (such as 
patent ownership, royalties, or financial gain greater than the minimum allowable by their institution) 
must fully disclose the nature of the conflict of interest in accordance with ACRIN Conflict of Interest 
policies and applicable federal, state, and local laws and regulations.  
 
 
13.0 
PUBLICATION POLICY 
Neither complete nor any part of the results of the study obtained under this protocol, nor any 
information provided to the investigator for the purposes of performing the study, will be published or 
passed on to any third party without the consent of ACRIN, the Study Chair, and/or the ACRIN 
ACRIN PA 4006 
28 
June 14, 2010 
 
 

 
Publication Committee. Any investigator involved in this study is obligated to provide ACRIN with 
complete test results and all clinical data obtained from the participants in this protocol. Investigators 
will follow the ACRIN Publication Policy (available online at www.acrin.org/PublicationsPolicy.aspx). 
 
 
 
14.0 
INSTITUTIONAL MONITORING AND AUDITS 
The investigator will permit study-related monitoring and auditing inspections of all study-related 
documents by the IRB, government regulatory agencies, and ACRIN. The investigator will ensure the 
capability for inspection of all participating sites’ study-related facilities (e.g. imaging centers, satellite 
sites). The investigator will allocate adequate time for these activities, allow access to all study-related 
documents and facilities, and provide adequate space to conduct these visits. 
 
14.1 
Monitoring  
Monitoring ensures protocol and regulatory compliance, participant’s welfare and safety, and provides 
resources to sites for clarification to the protocol and guidance in completion of the case report forms. 
(CRFs). Monitoring of the protocol is implemented after the activation of the trial, and once participants 
have been enrolled into the study at each site. Each site will be informed when the monitoring of the 
protocol is implemented. Monitoring instructions will be sent to the site prior to the implementation of 
monitoring to aid in preparation for the monitoring. The instructions will specify regulatory documents 
and participant case records scheduled to be monitored. The ACRIN QA Monitor will review CRFs and 
source documents at several different time points: after first few participants enrolled and during the 
conduct of the trial, including staff changes at the participating sites. The QA Monitor will review the 
initial, annual, and any revised regulatory documents during each monitoring phase.  
 
14.2 
Auditing  
All participating institutions that enroll participants will be audited. The timing of the initial on-site audit 
will depend upon several factors, including the rate of accrual (both study-wide and site-specific), the 
number of evaluable participants enrolled at an individual site, the status of the protocol and pending 
amendments, and monitoring status. Generally, audits will be conducted after the number of evaluable 
participants reaches 20% of targeted accrual, either study-wide and/or site-specific. Audits are typically 
scheduled to occur at least 3 months after an institution has been monitored, providing that monitoring 
did not identify issues that mandate immediate auditing. This schedule may be altered in the event of 
pending protocol amendments. Closure of the study to accrual will trigger auditing of all participating 
institutions not yet audited. Additionally, site-specific circumstances may prompt an audit at any time. 
 
Subsequent audits will be scheduled per the outcome of the initial audit. Audits can be completed more 
frequently and conducted on a yearly basis depending on the outcome of the audit and monitoring. The 
audits will be conducted per procedures established by ACRIN for the audit visit will be sent to the site 
prior to the scheduled audit visit. These instructions will specify which participant case records will be 
reviewed during the audit. On-site records will be verified against the submitted form, and the findings 
will be recorded on specially-prepared audit reports. Major discrepancies will be forwarded to the 
appropriate oversight body within ACRIN. IRB procedures, approvals, and ICFs will also be reviewed 
at the time of the audit visit. The ACRIN Audit Manual is available online at www.acrin.org.  
 
To help sites prepare for monitoring and audits and to assure that the investigator and the research staff 
maintain records appropriately, ACRIN Headquarters will offer training to sites. This training will cover 
all aspects of data collection, including special instructions to obtain and file the various source 
documents needed to verify the accuracy of submitted data for this trial. Details in the study-specific 
Monitor Plan and Audit Plan will override procedures and timing described in the protocol.  
ACRIN PA 4006 
29 
June 14, 2010 
 
 

 
 
14.3 
Source Documents  
Source data are found in all information, original records of findings, observations, or other activities in 
a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Source documents represent the first recording of any observations made or data 
generated about a study participant while he or she is enrolled in a clinical trial. Source documents for 
each study participant substantiate the data that are submitted to ACRIN. 
 
Source documents must verify the eligibility criteria and data submitted on all CRFs. If an item is not 
mentioned (e.g., history and physical examination alluding to a condition, but no mention of a 
psychological condition), it will be assumed it is not present. 
 
Research records for each case should contain copies of the source documents for the data collected and 
reported to ACRIN. If data are abstracted from medical charts that are not filed at the investigative sites 
(e.g. hospital charts), copies of these records should be filed in the research chart. Every attempt must be 
made to obtain all records/charts that were used to abstract any study data for this protocol. This will 
prevent any discrepancies and the inability to verify the document and the data reported.  
 
14.4  Case Report Forms 
CRFs, both web-based and paper forms, are the primary data collection instruments for the study. All 
data requested on the CRFs must be recorded, and any missing data must be explained. If a space is left 
blank on paper CRFs because the procedure was not done or the question was not asked, “N/D” must be 
noted. If the item is not applicable to the individual case, “N/A” must be noted. All entries on paper 
CRFs must be printed legibly in black ink on the paper CRFs. In the event of any entry errors, 
corrections must be made by drawing a single straight line through the incorrect entry, writing the 
initials of the person making the correction, recording the date when the correction is being made, 
and entering the correct data above the strike through. Do not use white out or an eraser. Please refer to 
ICH Good Clinical Practice Guidelines. 
 
Data elements that are extracted from the medical record (such as participant history or official clinical 
interpretations of images, pathology, or surgery results) and recorded on the CRFs will be reviewed 
against the appropriate component of the medical record. Data elements gathered from signed 
participant questionnaires must be available for review. Required study image interpretation data that are 
more detailed in information than the image and not typically documented in the standard radiology 
report may be documented on the CRF and are acceptable source documentation if signed by the 
Investigator. At the time of audit, the auditor will verify the occurrence of the imaging examination, the 
reader, and the date of the exam(s) from the medical record(s). Any use of approved CRFs as source 
documentation require a signature and date on the CRF with a reference to the information source 
(FFDM report, tomosynthesis report, medical record, etc.). Any use of CRFs as source documentation 
when the protocol has designated the source data will be medical record documentation will be 
considered a major protocol deficiency. 
 
14.5 
Institutional Review Board 
Sites must obtain initial full-board, local IRB approval to participate in ACRIN trials. Prior to 
participant registration, a copy of the IRB approval letter for the protocol and the ICF must be sent to 
ACRIN, along with a copy of the IRB-approved, site-specific ICF. Investigator will provide a copy(s) of 
IRB approval letter(s) for any amendment(s), and copy(s) of annual renewal(s). 
 
 
ACRIN PA 4006 
30 
June 14, 2010 
 
 

15.0 
STATISTICAL CONSIDERATIONS 
15.1 
Study Design and Endpoints 
Study participants will be recruited among those presenting for breast cancer screening using FFDM 
(Group A) or for diagnostic follow-up after positive findings on previous screening using FFDM (Group 
B) at ACRIN-qualified institutions in Pennsylvania that have a Hologic tomography scanner. Each
participant will undergo both FFDM and DBT examinations. Each of the two tests will be interpreted
separately by readers at the participating sites. Reference standard information on the presence or
absence of cancer at the time of screening will be determined by pathology and the 1-year follow-up.
15.2 
Specific Aims and Analysis Plans 
15.2.1 Primary Aim 
To compare recall rates of FFDM to the limited DBT set (digital breast two-view 
tomosynthesis with low-dose MLO) [Group A]. 
In this study, each participant will undergo imaging with both DBT and FFDM. To 
account for the paired nature of the design, McNemar’s test will be used to make the 
comparisons of call-back rates.   
15.2.2 Secondary Aims 
15.2.2.1 
To compare sensitivity of FFDM to the limited DBT set (digital breast two-
view tomosynthesis with low-dose MLO) [Groups A and B]. 
The sensitivities of the two modalities will be compared using McNemar’s 
test. The main analysis for this aim will be performed on the combined data 
from the two groups. In addition, data from each of the two groups will be 
examined separately. Exact p-values will be reported.  
15.2.2.2 
To assess lesion-type characterization: 
15.2.2.2.1 To compare the sensitivity and specificity by lesion-type characterization 
(calcification-only lesions versus soft-tissue lesions, as well as lesion 
subgroups: masses, calcifications, architectural distortions, asymmetries) 
in FFDM versus DBT (two-view tomosynthesis set with low-dose MLO) 
[Group A call-back cohort and Group B]. 
15.2.2.2.2 To estimate the agreement of FFDM and DBT with the determination of 
the adjudication committee on lesion-type characterization. 
The analysis for this aim will be performed at the lesion level. For the 
comparison of sensitivity and specificity, individual lesions will be 
grouped by lesion type as determined by the adjudication committee. For 
each group, sensitivity and specificity will be compared using 
McNemar’s test, adjusted for correlation in the lesion data due to 
clustering within the participant.12–14 For the assessment of agreement, 
the data on lesion-type determination of each modality will be tabulated 
against the determination by the adjudication committee. Percentages of 
agreement and kappa statistics appropriate for multiple categories will 
be estimated. 
ACRIN PA 4006 
31 
June 14, 2010 
 

 
15.2.2.3 
To use the sequential interpretation results [Groups A and B] in order to 
compare the two-view limited tomosynthesis set (with low-dose MLO view 
alone) with the tomosynthesis plus set (low-dose MLO view plus addition of 
low-dose CC view) on the basis of: 
• 
Call-back rate; 
• 
Identification of new lesion(s); 
• 
Lesion characterization; and 
• 
Triangulation.  
 
 
The analysis of this aim will utilize reader responses during the local 
sequential interpretation of the two-view tomosynthesis set with low-dose 
MLO, followed by sequential read with addition of low-dose CC view 
[Groups A and B]. Rates of interest will be estimated and compared. For 
analyses at the lesion level, adjustment for clustering of lesions by participant 
will be implemented. 
 
15.2.2.4 
To calculate and compare the radiation dose of the FFDM and the DBT sets. 
 
 
In the analysis for this aim, estimates of dose per participant will be 
computed. The radiation dose will be calculated in terms of the mean 
(average) glandular dose (MGD or equivalently AGD) from the kVp, mAs, 
target tube and filter, and other pertinent information derived from the 
DICOM header of the clinical images. The dose will be calculated per image 
and then summed to determine the total MGD per breast of the clinical FFDM 
images, and the total MGD per breast of the clinical trial-image DBT set. The 
distribution of radiation dose data will be explored graphically. Radiation 
doses from the two modalities will be compared non-parametrically, taking 
into consideration the paired nature of the design. 
 
15.2.2.5 
To identify the determinants of participant radiation dose and clinical image 
quality, including factors such as kVp, mAs, target/filter combination, and 
breast thickness and composition. 
 
 
In the analysis for this aim regression modeling will be utilized to examine the 
relation between participant radiation dose and variables representing the 
factors listed above.  
 
15.3 
Sample Size/Accrual Rate 
Study participants will be recruited to either Group A for breast cancer screening or Group B for 
diagnostic imaging following suspicious findings on previous breast cancer screening.  A total of 550 
participants (500 to Group A and 50 to Group B) will be enrolled over an accrual period of 12 months at 
two institutions. 
 
15.4 
Power Consideration 
The sample size for the study was chosen to provide adequate power for addressing the primary aim of 
the study, which is the comparison of call-back rates in Group A. Available data on the comparison of 
FFDM to DBT in general screening populations suggest that the call-back rate for FFDM is about 10% 
and that of DBT is about 6% to 7% (a 30% to 40% reduction in call-back rate between FFDM and 
DBT). The following table presents sample size computations to achieve power of 80% using a two-
ACRIN PA 4006 
32 
June 14, 2010 
 
 

 
sided McNemar’s test at level 0.05. Power and sample size are influenced by the actual difference in 
rates and by the proportion of cases in the off diagonal cells of the 2x2 table classifying call-back status  
as determined by FFDM and DBT.  
 
The table shows that a total sample size of 500 cases will provide adequate power for many parameter 
combinations of interest. Because the power of the test depends critically on the proportion of discordant 
call-back determination, which is difficult to assess a-priori, we plan to monitor this proportion during 
the early part of the study and consider adjustments in the sample size, if necessary. 
 
Sample Size
Difference 
in Call Back Rates 
Proportion of Discordant 
Determinations  
Power 
0.80103 
361 
0.030 
0.040 
0.80077 
463 
0.030 
0.050 
0.80053 
562 
0.030 
0.060 
0.80001 
645 
0.030 
0.070 
0.80022 
736 
0.030 
0.080 
0.80049 
830 
0.030 
0.090 
0.80033 
920 
0.030 
0.100 
0.80057 
258 
0.035 
0.040 
0.80076 
333 
0.035 
0.050 
0.80071 
410 
0.035 
0.060 
0.80093 
482 
0.035 
0.070 
0.80062 
543 
0.035 
0.080 
0.80013 
608 
0.035 
0.090 
0.80046 
676 
0.035 
0.100 
0.80085 
251 
0.040 
0.050 
0.80079 
307 
0.040 
0.060 
0.80044 
367 
0.040 
0.070 
0.80022 
421 
0.040 
0.080 
0.80038 
468 
0.040 
0.090 
0.80010 
517 
0.040 
0.100 
 
 
15.5 
Adjudication Committee Assessments  
Study-related imaging results will be assessed for lesion type (soft tissue or calcifications only) and 
subtype (mass, architectural distortion, calcifications, asymmetry) as determined by breast imaging 
experts (Drs. Conant and Copit) familiar with all modalities used in breast screening and diagnostics 
(inclusive of FFDM, tomosynthesis, ultrasound, MRI and x-ray mammography).  
 
15.6 
Reporting Guidelines 
Routine reports for this protocol will be provided to oversight bodies, including the ACRIN PA DSMB, 
for review during each of its quarterly teleconferences. 
 
Routine reports will include: 
• 
Accrual and participant characteristics; 
• 
Timeliness and completeness, eligibility and protocol compliance, and outcome data; 
• 
All reported adverse events. 
 
ACRIN PA 4006 
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June 14, 2010 
 
 

 
REFERENCES 
 
 
 
1. Poplack SP, Tosteson TD, Kogel CA, Nagy HM. Digital breast tomosynthesis: Initial experience in 
98 Women with abnormal digital screening mammography. Am J Roentgenol. 2007;189(3):616-623. 
2.  Rafferty E, Niklason L, Halpern E, et al. Late breaking multicenter clinical trials assessing 
radiologist performance using combined full-field digital mammography and breast tomosynthesis 
versus full-field digital mammography alone: results of a multi-center, multi-reader trial. 
[Radiological Society of North America 2007 abstract SSE26-02.]  
3. Gur D, Abrams GS, Chough DM, et al. Digital breast tomosynthesis: observer performance study. 
AJR Am J Roentgenol. 2009;193(2):586-591. 
4.  Good WF, Abrams GS, Catullo, et al. Digital Breast tomosynthesis: A Pilot Observer Study. Am J 
Roentgenol. 2008; 190:865-869 
5. Pisano ED, Gatsonis C, Hendricks E, et al. Diagnostic performance of digital versus film 
mammography for breast-cancer screening. N Engl J Med. 2005;353(17):1773-1783. 
6. Lewin JM, Niklason L. Advanced applications of digital mammography: Tomosynthesis and 
contrast-enhanced digital mammography. Semin Roentgenol. 2007;42(4):243-252. 
7. Rothenberg BM, Ziegler KM, Aronson N. Technology evaluation center assessment synopsis: full-
field digital mammography. J Am Coll Radiol. 2006;3(8):586-8.1.  
8.  Skaane P, Skjennald A. Screen-film mammography versus full-field digitcal mammography with 
soft-copy reading: randomized trial in a population-based screening program—the Oslo II study. 
Radiology. 2004;232:197-204. 
9.  Pisano ED, Gatsonis CA, Yaffe MJ, et al. American College of Radiology Imaging Network Digital 
Mammographic Imaging Screening Trial: objectives and methodology. Radiology. 2005;236:404-
412. 
10. ICRP Publication 60: 1990 Recommendations of the International Commission on Radiological 
Protection, 
1991. 
Annals 
of 
the 
ICRP. 
Volume 
21:1–3. 
Available 
online 
at: 
www.elsevier.com/wps/find/bookdescription.cws_home/29083/description#description; 
accessed 
June 3, 2010. 
11. National Council on Radiation Protection & Measurements (NCRP) Report No. 160: Ionizing 
radiation exposure of the population of the United States. 2009. Available online at: 
www.ncrppublications.org/Reports/160; accessed June 3, 2010. 
12. Eliasziw M, Donner A. Application of the McNemar test to non-independent matched pair data. Stat 
Med. 1991;10(12):1981–1991. 
13. Obuchowski NA. On the comparison of correlated proportions for clustered data. Stat Med. 
1998;17:1495–1507. 
14. Gönen M. Sample size and power for NcNemar’s test with clustered data. Stat Med. 
2004;23(14):2283–2294. 
  
 
ACRIN PA 4006 
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June 14, 2010 
 
 

 
APPENDIX I 
 
ACRIN PA 4006 
 
INFORMED CONSENT FORM TEMPLATE 
 
Comparison of Full-Field Digital Mammography with Digital Breast Tomosynthesis  
Image Acquisition in Relation to Screening Call-Back Rate 
 
 
[Note:  The American College of Radiology Imaging Network (ACRIN) complies with the privacy 
measures put forth by the Health Insurance Portability and Accountability Act (HIPAA).  
However, ACRIN does not monitor compliance with HIPAA; that is the responsibility of  
the local institutions and their Institutional Review Boards (IRBs). Local IRBs may choose  
to combine the authorization elements in the informed consent.] 
 
The American College of Radiology Imaging Network (ACRIN) is conducting a research study known 
as a clinical trial. Research staff will explain to you the details of what is involved. This document is 
designed to help you understand what will happen in the study, why the study is being done, and what 
risks or benefits might be involved in the study. This informed consent form must be signed before any 
study procedures are performed and before you are registered into the clinical trial. 
 
Clinical trials include only people who choose to take part. Please take your time in deciding whether 
you want to be involved. You are encouraged to discuss your decision with your friends and family. You 
can also discuss it with your health care team. If you have any questions, you should ask your study 
doctor for more explanation. If you decide to do this study, you will be asked to sign and date this form. 
 
You are being invited to participate in this research study because it is time for your routine breast 
cancer screening or you have recently been screened and are returning for diagnosis of suspicious 
findings.  
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to learn the safest way to use an imaging technology called tomosynthesis 
(called “study imaging” in this document) while getting images that will benefit you by showing 
potential breast cancers. Researchers will compare your study imaging with standard care using digital 
mammography, and other images taken to determine your breast health. They hope to determine the best 
way to obtain study images, which provide good information about your breast health while exposing 
you to no more radiation than routine x-ray mammography. Doctors are also trying to learn whether the 
study imaging can be used alone or should be used with digital mammography. 
 
About Tomosynthesis (Study Imaging) 
Mammograms provide two-dimensional (2-D), flat images. Tomosynthesis can be used to create three-
dimensional (3-D) images of the breast. The 3-D images may allow doctors to “scroll through” images 
of your breast to better see the layers of normal breast tissue that can sometimes appear to be concerning 
on regular 2-D mammography. This technique may see cancers that were hidden by normal tissue that 
overlaps on 2-D mammography. The study imaging will be completed after your standard imaging. If a 
separate machine is needed for the study imaging, then your breasts will be compressed again. Once you 
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are positioned in the machine, the study imaging will take about as much time as a routine 
mammography of both breasts. 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?  
About 550 women with no history of breast cancer will take part in this trial. This study will be 
conducted at approximately two (2) breast cancer screening institutions located in Pennsylvania.   
 
HOW LONG WILL I BE IN THE STUDY? 
You will be in the study up to 18 months from your initial breast screening. For the study, you are being 
asked to undergo study imaging immediately after routine imaging either for screening or for diagnosis. 
Your treating doctors will decide your treatment (for example, biopsy). Your study doctor and other 
research staff will contact you, a proxy if you are unavailable, and/or your treating doctor to learn about 
your health up to 18 months after your screening.  
 
This trial is expected to end after all study participants have completed the study-related visits and all 
follow-up information has been collected. This trial may be stopped at any time by your study doctor or 
by ACRIN without your consent for the following reasons:  
¾ Your health or safety may be at risk; 
¾ You have not been following study instruction; 
¾ An administrative decision has been made by ACRIN or the study doctor. 
 
These actions do not require your consent, but you will be informed of any of these decisions. 
 
You can stop participating at any time. Your decision to stop participating in the study will not interfere 
with your future medical care. However, if you decide to stop participating in the trial, we encourage 
you to talk to the study doctor and your treating doctor first.  
 
WHAT AM I BEING ASKED TO DO IN THE STUDY? 
If you agree to take part in this study and are determined to be eligible by research staff, you will be 
asked to read and sign this consent form before you are enrolled to participate in this trial and before any 
study procedures are performed. See the Schemas and Study Chart at the end of this section for a visit-
by-visit outline of what will be expected of you if you decide to participate in this trial. When you are 
enrolled into the study, you will have the following tests and procedures.      
 
Standard medical procedures that are part of regular standard of care and would probably be 
done even if you do not join the study: 
¾ A review of your medical history; 
¾ Digital mammography; 
¾ Diagnostic procedures. 
 
Medical procedures that are being done specifically because you are in this study (these may or 
may not be done if you do not join the study): 
¾ Study imaging (tomosynthesis) on both breasts; 
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June 14, 2010 
 
 

 
¾ Follow up for as along as 18 months—the research staff will want to access your medical 
records from your treating doctor. If you change treating doctor during this time, research 
staff may call you or a proxy to ask for contact information for your new treating doctor and 
perhaps ask about your breast health over the phone. 
 
If you agree to participate in this study, you will be assigned to one of two different study groups, 
depending on whether you are being screened for breast cancer (Group A: Screening) or are returning 
for further evaluation after screening (Group B: Diagnosis). 
 
For Group A: Screening   
If you are enrolled in Group A, you are going for your routine breast-cancer screening using digital 
mammography. You will receive the standard of care for this screening as determined by your study and 
treating doctors. You will also have study imaging called tomosynthesis. Your treating and study doctors 
may determine that no additional testing is needed after reviewing your image results; or, they may find 
it necessary to ask you to return for more imaging to diagnose suspicious findings that may be breast 
cancer. You will be asked to return for diagnosis if something suspicious is found on either digital 
mammography or study imaging. The study team will want to collect all of your images and results from 
screening and diagnostic studies.  
 
For Group B: Diagnosis 
If you are enrolled in Group B, you have already had your routine breast-cancer screening using digital 
mammography, and are returning to your treating doctor because of findings on the screening 
mammogram that were concerning and could possibly be due to a cancer. You will receive standard-of-
care imaging and will have additional study imaging called tomosynthesis. The study team will want to 
collect all of your images and results from screening and diagnostic studies.  
Most likely, you are returning for diagnosis of findings in only one breast. If you agree to join the trial, 
study imaging will take images of both breasts. If something concerning is found on study imaging, you 
may be asked to undergo more diagnostic procedures in either breast. Your treating doctor will then 
determine what additional steps may be needed, such as biopsy. Your treating doctor may make this 
decision based on findings from either standard diagnostic imaging or study imaging.  
 
Follow Up for Both Groups A and B 
The study doctor and research staff want to collect information on your breast health from your medical 
records up to 18 months after your screening visit. If you switch doctors during this time, it is important 
to let the study team know. Otherwise, they may need to contact you or, if necessary, a proxy (family 
member or someone who will know about your health) to learn how to contact your new treating doctor. 
At the very least, the research staff would like to know whether you are cancer free. If we cannot contact 
you or your treating doctor, the research staff may check national registries to learn about your health 
status. 
 
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STUDY SCHEMAS BY GROUP 
(Shaded boxes contain study-related procedures.) 
 
        GROUP A 
 
 
 
 
 
      GROUP B 
 
 
 
STANDARD CARE: 
Screening imaging finds 
suspicious findings 
Call Back  
for Diagnostic Imaging
PRIOR TO IMAGING: 
Eligibility and Registration 
 
 
DIAGNOSTIC IMAGING:  
o Standard digital mammography  
(one or both breasts, depending 
on screening results) 
o Study imaging, tomosynthesis 
(both breasts) 
o Possibly followed by additional 
standard imaging, such as 
ultrasound (one or both breasts, 
depending on previous imaging 
results) 
PRIOR TO IMAGING: 
Eligibility and Registration 
 
 
SCREENING IMAGING:  
o Standard digital mammography 
(both breasts) 
o Study imaging, tomosynthesis 
(both breasts) 
Call Back  
for Diagnostic Imaging
No Findings 
FOLLOW UP  
Research staff will review your medical records and collect follow-up images for up to 18 months 
after your initial screening visit. You may be contacted if you have changed treating doctors. 
STANDARD CARE:  
Clinical, standard  
diagnostic imaging 
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STUDY CHART 
 
PRIOR TO IMAGING:  
Group A and Group B 
Eligibility and Registration 
 
• 
Read and sign the informed consent form; 
• 
Provide medical history and demographic information; 
• 
Undergo pregnancy test if you are a woman of childbearing 
potential; 
• 
Provide telephone contact information for yourself and a 
proxy (someone who will be able to report on your health 
status). 
GROUP A IMAGING:  
Imaging for Screening  
 
 
• 
Confirm contact information; 
• 
Undergo imaging:  
- 
Standard-of-care screening imaging (both breasts); and 
- 
Study imaging (both breasts); 
• 
Answer questions about how you feel after the imaging.* 
• 
Confirm contact information; 
• 
Undergo imaging:  
- 
Standard-of-care diagnostic imaging (on one or both 
breasts, depending on your screening results); 
GROUP B IMAGING:  
Imaging for Diagnosis 
- 
Study imaging (on both breasts), and  
 
- 
Possibly other diagnostic assessment (such as  
ultrasound, again on one or both breasts,  
depending on imaging results); 
• 
Answer questions about how you feel after the imaging.* 
• 
Provide additional information related to your breast health 
up to 18 months after screening. Research staff may need to 
review your medical records and/or contact you, a proxy, 
and/or your treating physician to obtain this information. 
FOLLOW UP:  
Group A and Group B 
(Up to 18 Months  
After Screening)  
* If at any time within 30 days after study-related imaging, you have adverse effects you think may be related to the study, 
contact your study doctor and let him or her know. 
 
 
WHAT ARE THE POSSIBLE RISKS OR DISCOMFORTS OF THE STUDY? 
While on the study, you may be at risk for these side effects from the following procedures. You should 
discuss these with your study and/or treating doctor(s). There also may be other side effects that we 
cannot predict. Many side effects go away shortly after the imaging scan is stopped, but in some cases 
side effects can be serious, long lasting, or permanent.   
 
Risks Associated With Study Imaging (Tomosynthesis) 
Likely 
¾ Discomfort from breast compression that is similar to routine mammography; 
¾ Bruising similar to routine mammography. 
If you are in Group A, study imaging during screening may lead to additional findings compared with 
standard screening imaging alone. Suspicious findings on either set of images will mean you will be 
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asked to return for diagnosis. If you do not join the trial, your treating doctor will use standard screening 
imaging to determine whether you need to return or not. 
If you are in Group B, study imaging included for diagnosis may lead to additional findings and 
procedures compared with standard diagnostic imaging alone. You are agreeing for both of your breasts 
to undergo study imaging even though you may have been called back for diagnostic imaging on only 
one breast. This may lead to findings with study imaging that were not found during your initial 
screening visit. Therefore you may need to have additional diagnostic imaging of that breast. If you do 
not join the trial, your treating doctor will use standard imaging for diagnosis to determine whether you 
need further testing or not. 
 
Radiation Risks 
This research study involves exposure to radiation from the study imaging called tomosynthesis. In 
addition to the radiation you receive for your regular mammogram, you will be receiving a similar, 
second dose of radiation from the study imaging. The amount of radiation exposure will be largely 
dependent on your breast size. Your study doctor can explain how the dose might be higher for denser 
and larger breasts. Part of this study will look at radiation dose in hopes of obtaining quality images 
while optimizing radiation exposure to people in the future.  
 
This radiation dose is not necessary for your standard medical care and will occur only as a result of 
being in this study and undergoing study imaging. The dose that you will receive will very likely have 
no effects at all. Radiation doses much higher than what you will receive are known to increase the risk 
of developing cancer after many years.   
 
Reproductive Risks  
Because possible exposure to radiation can damage an unborn baby, you will need to inform your study 
doctor if you are pregnant or suspect that you may be pregnant. If you are pregnant, you will not be able 
to participate in this study. If you are unsure, you will need to have a negative pregnancy result per usual 
care prior to enrolling in this trial and throughout the trial prior to imaging if you are unsure of your 
pregnancy status.  
 
For more information about risks and side effects, ask your study doctor. 
 
WHAT ARE THE POSSIBLE BENEFITS OF TAKING PART IN THE STUDY? 
Taking part in this study may or may not benefit you. The results of the study imaging will be shared 
with your treating doctor. The study imaging for screening or diagnosis in this trial may improve your 
health by finding cancers not seen on standard imaging. On the other hand, study-related findings may 
lead to additional imaging or unnecessary treatment, such as biopsy. These risks are common in breast-
cancer screening and diagnostic imaging currently available. The hope is to reduce these risks in the 
future with better imaging through tomosynthesis. We hope the information learned from this study will 
benefit other women during breast cancer screening and diagnosis in the future. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT WANT TO PARTICIPATE? 
You may choose not to take part in this study. If you choose not to participate, there will be no penalty 
or loss of benefits to which you are otherwise entitled. Please talk with your study and/or treating 
doctor(s) about this and other options. 
  
 
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WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? 
We will do our best to make sure that your personal information will be kept private. However, we 
cannot guarantee total privacy. Your personal information may be given out if required by law. Records 
of your participation on this study, your progress, and images submitted while you are on the study will 
be kept in a confidential form at <<Institution>> and in a computer file at the headquarters of the 
American College of Radiology Imaging Network (ACRIN) in Philadelphia. All data sent to ACRIN 
over the Internet will be coded so that other people cannot read it. All personal identifiers are removed 
and replaced with a unique identifying number.  
 
You further understand and agree that authorized representatives of ACRIN, the Pennsylvania Dept. of 
Health, the Institutional Review Board (IRB) of <<Institution>>, and other groups or organizations that 
have a role in this study may, without obtaining additional consent from you, have access to and copy 
both your medical and research records, including the results of your participation in this study. This 
access is necessary to ensure the accuracy of the findings, the completion of the study, and your safety 
and welfare. If any publication or presentations result from this study, you will not be identified by 
name. Results will be reported in a summarized manner in which you cannot be identified. 
 
Your research records and images will be kept permanently on file at ACRIN and may be used for future 
research. All personal identifiers are removed and replaced with a unique identifying number. The 
studies that may be done with the information will not specifically help you. But, it might help people in 
the future who have or are at risk for breast cancer. 
 
WILL I HAVE TO PAY FOR ANYTHING? 
Taking part in this study may or may not lead to added costs to you or your insurance company.  Please 
ask your study doctor about any expected added costs or insurance problems. 
 
You and/or your health insurance will be charged for any portion of your care that is considered 
standard care. You and/or your insurance company will be charged for continuing medical care and/or 
hospitalization. You may be responsible for any co-payments and deductibles that are standard for your 
insurance coverage.  
 
You or your insurance company will not be charged for the following part of this research study:  
¾ Study imaging with tomosynthesis. 
 
You will receive no payment for taking part in this study. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor, <<insert name>>, if you feel that you have been injured 
because of taking part in this study or if any medical emergency, injury, or illness occurs during this 
study. You can tell the study doctor in person or call him/her at <<insert telephone number>>. 
 
In the case of medical emergency, injury, or illness during this study, emergency medical treatment is 
available but will be provided at the usual charge. You and/or your insurance will be responsible for the 
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June 14, 2010 
 
 

 
cost of the medical care of that illness or injury. There is no financial compensation that has been set 
aside to compensate you in the event of injury. 
 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
Taking part in this study is your choice. You may choose to or not to take part in the study. If you 
decided to participate, you are free to leave the study at any time. No matter what decision you make, 
there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will 
not result in any penalty or loss of benefits to which you are entitled. Your decision whether or not to 
participate in this study will not interfere with your future care. You can still get your medical care from 
our institution. 
 
During the study, we may find out more information that could be important to you. A Data and Safety 
Monitoring Board (an independent group of experts) may be reviewing the data from this research 
throughout the study. This includes information that might cause you to change your mind about being 
in the study. If information becomes available from this or other studies that may affect your health, 
welfare, or willingness to stay in this study, we will tell you about it as soon as possible. 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
(This section must be completed) 
You can talk with your study doctor(s) about any questions or concerns you have about this study. 
Contact your study doctor <<insert name>> at <<insert telephone number>>. 
 
This document explains your rights as a study participant. It you have any questions regarding your 
participation in this research study or you have any questions regarding your rights as a research 
participant, do not hesitate to speak with your study doctor or anyone listed below.  
 
For additional information about your health or in case of a medical emergency, you may contact: 
Usually the name of the local hospital information is provided and with instructions to study 
participants to inform the ER doctor of their participation in a clinical trial. 
 
 
 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
 
For information about your rights as a research subject, you may contact <<Institution Name>> 
Institutional Review Board (a group of people who review the research to protect your rights): 
(Provide the name of local IRB contact person) 
 
 
 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
 
WHERE CAN I GET MORE INFORMATION? 
For more information, you may also visit the American College of Radiology Imaging Network web 
site, www.acrin.org. For more information about Tomosynthesis, you can go to the Patients section of 
the ACRIN web site.  
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ACKNOWLEDGEMENT 
When you sign this document, you are agreeing to take part in this study. This means you have read all 
the above information, asked questions regarding your participation, and received answers that you 
understand to all your questions. You have also had the opportunity to take this consent form home for 
review or discussion if you want to.  
 
You willingly give your consent to participate in this study. A copy of this signed informed consent 
form will be given to you.  
 
 
 
 
 
 
 
 
Printed Name of Study Participant/ 
Signature 
Date 
Legal Representative 
 
<Insert other signature and date lines as appropriate per local IRB policies and procedures> 
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APPENDIX II 
 
ACRIN PA 4006 
 
SUPPLEMENTAL MATERIALS AVAILABLE ONLINE 
 
 
Supplemental materials that support the conduct of the trial are available on the ACRIN web site at the 
ACRIN PA 4006 protocol web page (www.acrin.org/4006_protocol.aspx). Types of materials posted 
include: 
 
¾ Application and protocol activation documents (General Qualifying and Protocol Specific 
Applications, protocol activation checklist, etc.);  
¾ Data forms; 
¾ Imaging materials (Image Transmittal Worksheet), available directly via 
www.acrin.org/4006_imagingmaterials.aspx;  
¾ Recruitment and education materials; 
¾ Regulatory resources, available directly via www.acrin.org/pdrc.aspx; 
¾ Participating site list.  
 
For more information related to the trial, contact the ACRIN PA 4006 Contact Personnel link on the 
above-mentioned web page for a list of protocol team members at ACRIN Headquarters and their roles. 
 
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