SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Digital Breast Tomosynthesis Mammography System

Device Trade Name: ASPIRE Cristalle Digital Breast Tomosynthesis Option

Device Procode: OTE

Applicant’s Name and Address: FUJIFILM Medical Systems U.S.A., Inc.

419 West Avenue
Stamford, Connecticut 06902

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P160031

Date of FDA Notice of Approval: January 10, 2017

II. INDICATIONS FOR USE

The Fujifilm ASPIRE Cristalle with Digital Breast Tomosynthesis (DBT) Option
acquires and generates FFDM and DBT images, and is intended for use in the screening
and diagnosis of breast cancer.

A screening examination may consist of sets of CC and MLO images acquired in:
• the FFDM mode only, or
• an FFDM image set and a DBT image set acquired in the ST (standard) mode.
The FFDM image set and the DBT image set must be acquired with N-mode dose
setting, and may be acquired in one compression (Tomo Set mode) or separate
compressions (FFDM and DBT modes).

III. CONTRAINDICATIONS

There are no known contraindications.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the ASPIRE Cristalle Digital Breast
Tomosynthesis Option labeling.

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V. DEVICE DESCRIPTION

The Fujifilm ASPIRE Cristalle system (Model: FDR MS-3500) is an integrated digital
mammography system. It consists of two main subsystems and has three operating
modes.

A. Main subsystems

1) The FDR-3500DRLH X-ray Stand (Exposure Unit) is an integrated x-ray

delivery system consisting of the FDR-3500H (exposure stand) and FDR-
3000DRL (flat panel detector and control cabinet).

2) The FDR-3000AWS Acquisition Workstation (AWS) controls the exposure

unit to acquire and process mammographic images. With it, the operator
registers patient identifying information, selects exposure condition, displays
study information, edits patient identifying information, displays studies and
confirms image quality. The FDR-3000AWS is configurable with several
monitor options.

B. Operation modes

The FDR MS-3500 has three selectable modes of operation. A single common
detector and x-ray tube are used for all of the modes. The 1) full-field digital
mammography (FFDM) mode is FDA-cleared (K133972) and is standard. This PMA
is for two additional modes to be enabled upon FDA approval by a software upgrade
and comprise the DBT Option: 2) the DBT mode and 3) the Tomosynthesis Set menu
(Tomo Set menu) mode.

1) The standard FFDM mode produces conventional two-dimensional FFDM images

of the breast. Both CC and MLO screening views and diagnostic views may be
acquired at either the L- (Low), N- (Normal) or H- (High) mode dose setting.

2) The optional DBT mode captures the three-dimensional (3D) DBT images of the
breast by taking multiple low-dose images per view along an arc over the breast.
All images are acquired in the ST (standard) DBT mode with N-mode dose
setting only. During acquisition, the x-ray tube moves approximately 1 degree for
each image in a 15° arc (-7.5° to +7.5°) above the compressed breast, acquiring
15 images in approximately four (4) seconds. These acquired projection images
are reconstructed for interpretation as cross-sectional “slices” of the breast, with
each slice typically 1-mm thick. The DBT image set may be acquired for the CC,
MLO and other views of the breast.

3) The optional Tomosynthesis Set menu (Tomo Set menu) mode combines the
FFDM and DBT modes during a single compression of the breast, acquiring the
DBT images in ST mode and N-mode dose and FFDM image with N-mode dose.

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VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for breast cancer screening and diagnosis. These
include clinical breast examination, film-screen mammography, full-field digital
mammography, contrast enhanced spectral mammography, ultrasound, dedicated breast
CT and magnetic resonance imaging.

The Hologic Selenia Dimensions 3D System, the GE SenoClaire, and the Siemens
MAMMOMAT Inspiration, approved by FDA via PMA P080003, PMA P130020, and
PMA P140011 respectively, can also produce DBT images.

After detection of an abnormality, a biopsy and pathology examination may be performed

to diagnose the cancer. Each alternative has its own advantages and drawbacks. Patients
should fully discuss these alternatives with their physician to select the method that best
meets expectations and lifestyle.

VII. MARKETING HISTORY

The ASPIRE Cristalle DBT Option which is known outside of the United States (OUS)
as the AMULET Innovality Tomosynthesis Option, has never been withdrawn from OUS
marketing for reasons related to safety or effectiveness. The AMULET Innovality system
has been marketed in Japan, Germany, France, Belgium, Italy, Spain, Portugal, United
Kingdom, Poland, Netherlands, Israel, Sri Lanka, Morocco, Tunisia, Taiwan, Uruguay,
South Africa, Malta, China, Thailand, Hungary, Denmark, Australia, Greece,
Switzerland, Norway, Sweden, Turkey, Argentina, Ecuador, Columbia, Mexico, Bolivia,
India, Australia, Singapore, Philippines, Myanmar, United Arab Emirates (UAE), Egypt,
and Lebanon.

VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

No serious adverse events were reported for the patients enrolled in the clinical study.
However, potential adverse effects of any mammography system include or arise from:
• excessive breast compression
• excessive x-ray exposure
• electric shock
• infection
• skin irritation, abrasion, or open skin wound

One minor adverse event and no serious adverse event was reported for the patients enrolled
in the clinical study. For more information on the minor adverse event that occurred in the
clinical study, please see Section X below.

Failure of the device to perform as expected or failure of the physician to correctly interpret
the images produced by the device may lead to improper patient management decisions.
False positives could lead to additional exams that could result in a small risk of additional

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 discomfort and complications such as infection or bleeding if a biopsy were performed. The
risk of a serious complication is extremely low. False negatives would not be recalled which
may result in delay in diagnosis and progression of disease up until the next screening exam
or interval diagnosis.

IX. SUMMARY OF NONCLINICAL STUDIES

A. Physical Laboratory Studies

Where applicable to the assessment of the imaging characteristics of a digital breast

tomosynthesis system, FUJIFILM Medical Systems U.S.A., Inc. (also referred to as the
“applicant”) followed the physical laboratory testing methods in the FDA guidance, Class
II Special Controls Guidance Document: Full-Field Digital Mammography System. When
applicable, the applicant followed the EUREF Protocol for the Quality Control of the
Physical and Technical Aspects of Digital Breast Tomosynthesis Systems (Version 1.0,
March 2015), the applicant also performed physical performance testing to address the
device characteristics and image reconstructions that are specifically applicable to DBT.
• Table 1. Physical Laboratory Testing (applicable to Tomosynthesis)
• Table 2. Modulation transfer function in projection image and reconstructed image
• Table 3. Average Glandular Dose (AGD)
• Figure 1. Relative in-plane MTF (ST mode, 100 µm pixel size)
• Figure 2. CDMAM phantom scoring (ST mode, 100 μm pixel size)

Table 1. Physical Laboratory Testing (applicable to Tomosynthesis)

Acceptance
Test Purpose Results
Criteria
Assess detector signal Linearity of the The output signal level
1. Sensitometric
Response response versus radiation digital value is linear relative to
exposure level versus radiation exposure
exposure level

2. Spatial
Resolution
A quantitative measure of No criteria – Table 2. Modulation
• Projection
the spatial resolution System transfer function in
MTF
properties of the image Characterization projection image and
acquisition system. reconstructed image
A quantitative measure of No criteria –
• Reconstructed Figure 1. Relative in-
the in-plane spatial Follow the ACR
Image In- plane MTF (ST
resolution properties of the phantom
Plane mode, 100 μm pixel
reconstructed image. evaluation
Resolution size)

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 Acceptance
Test Purpose Results
Criteria
A quantitative measure of 10.0 mm FWHM in 1shot
• Reconstructed
the z-resolution properties ± 1.0mm Phantom M Plus
Image Z-
of the reconstructed image. 24x30 evaluated by
Resolution
Tomo QC Calculation
Tool. The result was
10.0mm ± 1.0mm
within the criteria.
A quantitative measure of No criteria – NPS responds linearity
3. Noise Analysis
the noise properties as System to the exposure. It
described by the noise Characterization shows x-ray quanta
power spectrum (NPS) as a noise is dominant.
function of spatial
frequency and exposure
level
A quantitative measure of No criteria – DQE result shows it is
4. Signal-to-Noise
Ratio Transfer – the efficiency of signal-to- System almost constant from
noise ratio (SNR) transfer Characterization 0.01mGy to 0.04mGy.
DQE
by calculating the detective
quantum efficiency (DQE)
as a function of spatial
frequency.

5. Dynamic Range
A quantitative measure of Linearity of NEQ is linear relative
• NEQ
the noise properties as NEQ versus to exposure.
described by the noise exposure level
equivalent quanta (NEQ)
as a function of exposure
level
A quantitative measure of Almost constant DQE is almost
• DQE
the efficiency of signal-to- constant against
noise ratio (SNR) transfer exposure.
by calculating the detective
quantum efficiency (DQE)
as a function of exposure
level.
Not applicable -For Not applicable Image readout is
6. Fading
systems using a delayed accomplished
readout of image data immediately after x-
ray exposure,
therefore, fading
testing is not
applicable

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 Acceptance
Test Purpose Results
Criteria
Assessment of ghost on Ghost image The ghost factor for
7. Repeated
successive exposure factor should be ST mode was 0.06
Exposure and
below 0.3. well below 0.3.
Image Erasure
It was evaluated in
Tests
accordance with
EUREF 4th Edition.
8. Automatic
Exposure
Control
Performance
A quantitative measure of Not to exceed Table 3. Average
• AEC
Average Glandular Dose 3.0mGy per view Glandular Dose
performance
(AGD) as a function of with 4.2cm of (AGD). Well below
breast thickness. 50% glandular the MQSA limit.
and 50% adipose
composition
breast which is
the MQSA limit
for screening.
Detectability of small MQSA Tomosynthesis scans
• Phantom
structures in the breast minimum using AEC (automatic
Testing -
requirement – exposure control)
ACR MAP
Perfect phantom settings at W/Al
scores values anode/filter at 26, 30
are: 6, 5, 5. and 33 kV, in 20mm,
Passing phantom 42mm, and 60mm,
scores values respectively, were
are: 4, 3, 3. evaluated by a group
of experienced human
observers. The
following are the
average score values
(100 µm pixel size):
5.8, 4.0, 4.5 at 20mm,
5.0, 4.0, 4.0 at 42mm
and 4.8, 3.8, 3.8 at
60mm for fibers,
speck groups, masses,
respectively.

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 Acceptance
Test Purpose Results
Criteria
Detectability of contrast No criteria –
• Phantom
details of structures in the Evaluation of Figure 2. CDMAM
Testing -
breast CDMAM is phantom scoring (ST
CDMAM
under discussing mode, 100 µm pixel
in the relevant size).
society such as
EUREF.

A quantitative estimate of Not exceed Tomosynthesis testing

9. Patient Radiation
the patient radiation dose 3.0mGy at 4.2 simulated 4.2cm thick
Dose
as the average glandular cm and 50% compressed breasts
dose. glandular and consisting of 50
50% adipose percent glandular and
composition 50 percent adipose
phantom in the tissue. The measured
cc- projection AGD was 1.2 mGy for
per MQSA ST mode N-mode,
requirements. well below the MQSA
limit.
The minimum and Current standard The measured
10. Breast
maximum powered of care compression force did
Compression
compression force recommends that not exceeded 200N,
System
the maximum when 200N which is
compression the maximum value
force be set to which can be set was
clinical applied.
parameters such
as skin tautness,
breast anchoring,
patient tolerance,
etc.
Assess fidelity in the Not exceed ± 2% The distortion was
11. Geometric
mapping of geometrical taking into around 0.3%, well
Distortion
lengths inside individual account of below the criteria.
(Reconstructed
slices geometric
Image)
magnification.
Grayscale uniformity Within -30% The minimum CNR
12. Uniformity
inside individual slices is relative to the was -16% (100 µm
Reconstructed
assessed using spatially CNR of ROI at pixel size) within the
Slice with CNR
homogeneous PMMA the center of the criteria.
blocks chest wall side.

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 Acceptance
Test Purpose Results
Criteria
Assess x-ray exposure field X-ray field The measured x-ray
13. Collimation
extends to the field was within the
Assessment/
edge of the criteria.
Breast Support
patient support
Alignment in
of chest wall side
Projection Mode
within 2mm.
Does not extend
to the edge of the
patient support
for other sides.
-based on IEC
60601-2-45

Table 2. Modulation transfer function in projection image and reconstructed image

Spatial Projection image Reconstructed image
frequency in-plane in-plane resolution
resolution
150µm 100µm 150µm
of Horizontal Vertical Horizontal Vertical
Horizontal and
Vertical
1 0.89 0.94 0.65 0.90 0.62
2 0.75 0.63 0.09 0.64 0.09
3 0.39 0.20 0.02 0.31 0.02

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 Figure 1. Relative in-plane MTF (ST mode, 100 µm pixel size)

Table 3. Average Glandular Dose (AGD)

PMMA Thickness (mm) Tube Voltage (kV) Tube Load (mAs) AGD (mGy)
20 mm 26 kVp 36 1.0 mGy
30 mm 28 kVp 32 0.9 mGy
40 mm 30 kVp 40 1.3 mGy
45 mm 32 kVp 40 1.6 mGy
50 mm 33 kVp 42 1.7 mGy
60 mm 36 kVp 50 2.6 mGy
70 mm 37 kVp 63 3.2 mGy

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 [ST] Predicted Threshold Contrast Measurements
(error-bar:5%)

4.50

4.00
Threshold gold thickness (um)

N-mode
3.50

3.00

2.50

2.00

1.50

1.00

0.50

0.00
0.00 0.20 0.40 0.60 0.80 1.00

Detail Diameter (mm)

Figure 2. CDMAM phantom scoring (ST mode, 100 µm pixel size).

B. Additional Studies

Conformance to Voluntary Standards

The applicant provided certificates of conformance to the following voluntary
standards:
• AAMI / ANSI ES60601-1:2005/(R)2012 And C1:2009/(R)2012 And,
A2:2010/(R)2012
• IEC 60601-1-2 Edition 3: 2007-03
• IEC 60601-1-3 Edition 2.0 2008-01
• IEC 60601-2-45 Edition 3.0 2011-02
• ISO 10993-1 Fourth edition 2009-10-15
• IEC 62304 First Edition 2006-05
• ISO 14971 Second Edition 2007-03-01
• NEMA PS 3.1 - 3.20 (2011)

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 Software-Related Documentation
The applicant provided design and software testing documentation consistent with
FDA’s Guidance for the Content of Premarket Submissions for Software Contained
in Medical Devices and Content of Premarket Submissions for Management of
Cybersecurity in Medical Devices. The applicant conducted software unit testing and
integration testing to verify that all the sub-systems satisfy the software requirements
and integrated successfully. System testing was also conducted to validate that the
software specifications conform to its intended use and user requirements. The
applicant conducted regression testing to ensure that new software features introduced
by the tomosynthesis option do not create problems with previous version of the
software. All the test activities were completed successfully. The impact of the
unresolved anomalies on device safety and effectiveness were properly assessed. The
mitigations for the unresolved anomalies were provided and acceptable.

C. Conclusion of Non-Clinical Studies

Physical laboratory testing and the conformance to the voluntary standards demonstrated
that the ASPIRE Cristalle DBT option can be used to produce diagnostic quality DBT
images.

X. SUMMARY OF PRIMARY CLINICAL STUDY(IES)

The applicant performed clinical studies to establish a reasonable assurance of safety

and effectiveness of the ASPIRE Cristalle DBT Option for breast cancer screening and
diagnosis in the US. Data from these clinical studies were the basis for the PMA
approval decision. A summary of the clinical studies is presented below.

A. Study Design

Patients were enrolled between June 30, 2014 and December 30, 2015. The
studies included a prospective image acquisition study in which subjects were
imaged with the investigational device in addition to their standard of care, and a
retrospective multiple-reader multiple-case (MRMC) pivotal reader study.

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 Table 4. Clinical Studies
Study Study Study Objective Number of Number of Clinicaltrials.g
Design Sites/ Subjects ov Registration
Readers #
Image Prospectiv • Subject accrual for 5 1232 NCT02156258
Acquisition e subject blinded reader enrollment subjects
accrual studies sites
• Evaluate the safety
of the device
Pivotal Retrospect • Evaluate the safety 28 readers 300 cases NCT02692209
MRMC ive reader and effectiveness (60 cancers,
Study study of the device. 49 benign
• Establish that biopsy
FFDM + DBT has cases, 72
superior diagnostic recall
accuracy as subjects,
compared to and 119
FFDM alone. normal
cases)

Prospective Case Accrual

The applicant designed and conducted a prospective case accrual study to collect
FFDM and DBT images of patients undergoing either a routine screening
mammogram, undergoing diagnostic work-up after a potential anomaly was detected
at screening, or scheduled for a biopsy of a suspicious finding

A total of 1232 subjects were enrolled from five United States clinical trial sites under
IRB approval for the image acquisition protocol entitled: FMSU2013-004A:
“Acquisition of Digital Mammography and Breast Tomosynthesis Images for Clinical
Evaluation of Fujifilm Digital Breast Tomosynthesis”.

For all subjects, in addition to their standard of care imaging, mediolateral oblique
(MLO) and craniocaudal (CC) DBT images were acquired followed immediately in
the same compression by the acquisition of the FFDM image of the same breast view,
for a total of eight images per subject. Both the FFDM and DBT images were
collected in digital format by the applicant.

1. Clinical Inclusion and Exclusion Criteria

Inclusion Criteria
Subjects enrolled must have met all the following inclusion criteria:
• Screening Subjects
o Be at least 40 years of age, are
o Asymptomatic,

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 o Scheduled for a routine screening mammogram,
• Recall Subjects
o Be at least 18 years of age,
o Received a BIRADS 0 within the last 60 days
o Are recalled for additional imaging
• Diagnostic Subjects
o Be at least 18 years of age,
o Had a screening mammogram within the last 60 days, been given a BI-
RADS® 0 and are recalled for additional imaging and are given a BI-
RADS® 4 or 5, or have had a four-view mammogram within the last
60 days for clinical concerns and been given a BI-RADS 4 or 5, and
scheduled for biopsy.
• Have the ability to understand the requirements of the study, to provide
written informed consent, and to comply with the study protocol, and
• Meet none of the exclusion criteria.

Exclusion Criteria
Subjects were excluded from participating in the study if they meet any one or
more of the following exclusion criteria:
• Presence of a breast implant.
• Women with only a single breast; for example, post mastectomy patients.
• Is pregnant or believes she may be pregnant.
• A woman who had recently delivered and who has expressed the intention to
breast-feed or is currently breast-feeding.
• A woman who has significant existing breast trauma within the last one year.
• Has self-reported severe non-focal or bilateral breast pain affecting subject’s
ability to tolerate digital mammography and/or breast tomosynthesis
examinations.
• A woman who has had a mammogram performed for the purpose of therapy
portal planning within the last year.
• Cannot, for any known reason, undergo follow-up digital mammography
and/or breast tomosynthesis examinations (where clinically indicated) at the
participating institution.
• Is an inmate (see United States Code of Federal Regulations 45CFR46.306)

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 2. Follow-up Schedule
All patients with normal mammograms were asked to return for confirmatory
standard of care mammograms at one year to confirm non cancer status. Subjects
that underwent biopsies and had pathology results were not required to return one
year later. The one year follow-up or pathology result determined the subject’s final
clinical diagnosis for the study. Subjects that had a negative/benign mammogram or
benign biopsy were classified as having a final diagnosis of “no cancer”. All cancer
mammograms were confirmed by a biopsy proved pathology report. Discovery of a
cancer at any time up to and including the one year examination resulted in the
subject being assigned a final diagnosis of cancer.

3. Clinical Endpoints
Successful demonstration of the safety and effectiveness of the ASPIRE Cristalle
DBT Option (Fujifilm DBT system) is defined as the per-subject average AUC
for FFDM + DBT being statistically significantly superior to the average AUC for
FFDM at statistical significance level alpha = 0.05, which is established if the
lower limit of the two-sided 95% CI for the difference in average AUC for FFDM
+ DBT minus FFDM lies entirely above zero (0).

B. Accountability of PMA Cohort

At the time of database lock, a total of 1232 patients were enrolled on the image
acquisition protocol. Eleven (11) subjects were ineligible (0.9%), and 153 eligible
subjects were not evaluable (12.4%; Figure 3). The set of 1068 eligible and evaluable
subjects includes 222 subjects with cancer (20.8%=222/1068). Eighty (80) of the
eligible and evaluable Recall subjects and 17 of the eligible and evaluable Negative
subjects are still being followed through one-year imaging (9.1%=97/1068). Among the
Recall subjects 68 are within the 455 day follow-up window as of the last data transfer
and 12 are overdue; among the Negative subjects these numbers are 3 and 14,
respectively.

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 1232 Enrolled

11 Ineligible (0.9%):
Pathway requirements not met (n = 8),
Presence of an implant (n = 1),
Single breast (n = 1),
Currently breast-feeding or intends to
breast-feed (n = 1)

1221 Eligible

153 Unevaluable (12.4%):

Lost to follow-up (n = 104),
Study procedure was not performed (n =
25),
Images not acceptable (n = 21),
Subject withdrew consent (n = 2),
Other* (n = 1)

1068 Eligible and Evaluable (86.7%)

Reference Standard:
222 Cancer,
435 Benign,
11 Atypical/High Risk,
1 Biopsy Inconclusive,
144 Recall,
238 Negative,
17 Unknown

*Other reason for unevaluability: PATIENT CONSENTED ON 04/27/15,

ADDITIONAL IMAGES WERE FROM OUTSIDE FACILITY PRIOR
TO DATE OF ENROLLMENT (04/27/15)

Figure 3. Accountability of Subject Cohort: N

Pivotal MRMC Reader Study

The applicant designed and conducted a retrospective pivotal MRMC study using a
unique enriched subset of cases accrued from the prospective image acquisition
study. The objective of this study was to demonstrate the superiority of the FFDM
+ DBT to FFDM only for the detection of breast cancer.

Pivotal Study Cohort and Baseline Parameters

A total of 298 cases (59 cancer cases and 239 non-cancer cases) were randomly
selected and included in this pivotal reader study from the library of FFDM and

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 DBT mammograms collected under the image acquisition protocol. All cancer
cases were truthed. The 239 non-cancer cases were comprised of:
• 49 biopsy proven benign cases,
• 71 recall cases, and
• 119 normal cases.
Cases were randomly selected to avoid selection bias and to provide
representative distributions of breast density, finding types, and equal distribution
across enrolling sites. The case data included in this pivotal study were different
than the cases used in the training cohort. The 191 normal and recall cases were
selected and used in the reader study before the one year follow up on all cases
were collected.

C. Study Population Demographics and Baseline Parameters

The demographics of the study population in terms of breast density and
cancerous lesion characteristics were typical of the United States screening
population (see Tables 5, 6, and 7, below).

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 Table 5. Characteristics of Study Sample: N (%) unless otherwise noted
Total (N = 298)
Site
T01 84 (28%)
T02 57 (19%)
T03 50 (17%)
T04 55 (18%)
T05 52 (17%)
Enrollment Pathway
Screening 120 (40%)
Recall 79 (27%)
Diagnostic 99 (33%)
Age
Median (IQR) 56 (49 - 65)
Range 20 – 82
Mean (SD) 56.5 (10.7)
Race
American Indian or Alaska Native 3 (1%)
Asian 1 (< 1%)
Black or African American 23 (8%)
White 269 (90%)
Other/Unknown* 2 (1%)
Ethnicity
Hispanic or Latino 25 (8%)
Not Hispanic or Latino 268 (90%)
Unknown/Not Reported 5 (2%)
Breast Composition (Density)
a. Almost entirely fatty 29 (10%)
b. Scattered areas of fibroglandular density 132 (44%)
c. Heterogeneously dense 115 (39%)
d. Extremely dense 22 (7%)
Number of Lesions
0 117 (39%)
1 154 (52%)
2 22 (7%)
3 5 (2%)
Reference Standard Status
Cancer 59 (20%)
Benign 49 (16%)
Recall 71 (24%)
Negative 119 (40%)
Header N applies unless otherwise provided. IQR = interquartile range, 25th
percentile through 75th percentile. SD = standard deviation.
All subjects are Female.
*Race Other/Unknown = ITALIAN (n = 1), UNKNOWN (n = 1).
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 Table 6. Characteristics of Cancer Cases: N (%) unless otherwise noted

Total (N = 59)
Histology
IDC with DCIS (2 lesions) 1 (2%)
IDC (2 lesions) 2 (3%)
ILC (2 lesions) 1 (2%)
IDC; DCIS 2 (3%)
DCIS (2 lesions) 3 (5%)
IDC with DCIS 5 (8%)
IDC 19 (32%)
ILC 4 (7%)
DCIS 21 (36%)
Other* 1 (2%)
Size (mm, maximum)
N 55
Median (IQR) 16.0 (10.0 - 23.0)
Range 2.0 - 90.6
Mean (SD) 19.03 (13.92)
Lesion Type(s)
Soft Tissue Lesion(s) Only 28 (47%)
Soft Tissue Lesion(s) and Calcifications 10 (17%)
(separate and/or associated)
Calcifications Only 21 (36%)
Header N applies unless otherwise provided. IQR = interquartile range, 25th
percentile through 75th percentile. SD = standard deviation.
IDC = invasive ductal carcinoma. ILC = invasive lobular carcinoma. DCIS = ductal
carcinoma in situ.
*Other histology = Papillary carcinoma cannot rule out invasion.
Table 7. Characteristics of Benign Cases: N (%) unless otherwise noted

Total (N = 48*)
Size (mm, maximum)
N 39
Median (IQR) 10.0 (7.0 - 14.0)
Range 3.0 - 57.0
Mean (SD) 12.91 (10.74)
Lesion Type(s)
Soft Tissue Lesion(s) Only 24 (50%)
Soft Tissue Lesion(s) and 4 (8%)
Calcifications (separate and/or
associated)
Calcifications Only 20 (42%)
*Excludes one case for which we lack lesion information because this case is Benign based
on a biopsy at one-year follow-up on the Image Acquisition protocol.
IQR = interquartile range, 25th percentile through 75th percentile. SD = standard deviation.

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 Reference Standard
The reference standard for a cancer case is a case in which at least one lesion is
confirmed as malignant by biopsy or surgery.
The reference standard for a non-cancer case was biopsy, surgery, or
interpretation by radiologists at the enrolling site:
 Biopsy proven non-cancer case
 Non-cancer case with reportable findings (“recall”)
 Non-cancer case with no reportable findings (“normal”)
Cancer cases: ground truth (GT) for the type and location of cancer cases were
based on the mammography findings described by the radiologist at the clinical
site and supported by the radiology and the pathology report from biopsy
procedures. GT FFDM and DBT images with lesion locations marked
electronically were created by an independent radiologist based on review of the
electronic case report forms (eCRFs), radiology and pathology reports.
Readers
28 readers were involved in this pivotal study. The readers had a variety of
experience ranging from breast imagers to general radiologists, with and without
DBT experience, and represented academic and nonacademic institutions.
Readers were board certified and MQSA-qualified.

Prior to the blinded reading session, all readers took part in a training, which
provided an overview of DBT physics, the specific features of DBT, and the
differences between FFDM and DBT. After being trained on the use and features
of the ASPIRE Bellus workstation, the readers reviewed approximately 50 FFDM
images with corresponding DBT images of various breast pathologies and
densities with the training radiologist. Additionally, the flow of the sequential
reading session (FFDM first, then FFDM + DBT) was explained as well as how
interpretation data should be recorded in the eCRFs. The readers then
independently interpreted 40 cases of various breast pathologies and densities.
The training radiologist reviewed and provided direct feedback to the readers for
these 40 cases. The readers then independently interpreted 60 cases of various
breast pathologies and densities. No feedback was provided for this case set.
None of the readers were excluded from the primary analysis since readers are not
subjected to any cancer detection test in clinical practice.

Blinded Reading Sessions

The readers were told that the samples of cases do not represent a standard
screening population, and were blinded to the actual distribution and nature of the
set of images they were asked to review. Readers were masked to the results of
the reference standard and image acquisition interpretations for each case.
Readers did not have access to prior mammograms or other clinical information.
All readers performed their interpretations independently.

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 19

 Each study reader was randomly assigned to a unique reading order. All study
readers interpreted all study cases in a sequential format, with FFDM only first
and then FFDM + DBT. Readers interpreted the randomized preloaded
mammograms in their assigned order.

Readers were assisted by scribes, who entered each reader’s responses in the
electronic reader case report forms. The reader completed the eCRFs for each case
for the two reads. For each read, the reader first reported whether there were any
reportable findings:
• If the answer to this question was “no” the reader was asked to choose for this
case: a BI-RADS assessment category of either 1 or 2, and a Probability of
Malignancy (POM) score following the POM guidance provided (see below) as
reference (radiologists were allowed full range of POM scoring), and recall
decision of “no”.
• If the reader answered “yes” as to whether there were reportable findings, the
reader was asked to confirm assignment of an initial BI-RADS assessment
category of 0, and then provided detailed information on for up to three
suspicious findings:
o Location (including breast, view, quadrant locations and x/y/slice coordinates,
if possible)
o Type, as mass, asymmetric density, focal asymmetry, microcalcifications,
other; Radiologist may check all that apply.
o “Forced” BI-RADS assessment category 1, 2, 3, 4, or 5
o POM score 0 through 100%
o The reader was then asked for an overall: recall decision, forced BI-RADS
assessment category, and POM score, for the case.

A study monitor representing the sponsor reviewed the information recorded

(eCRF’s) for completeness.
In cases with reportable findings, consistency of BI-RADS scores, POM
scores, and recall decisions were not forced – e.g., readers were permitted to
use the full range of POM scores for a finding (following the POM guidance)
no matter what BI-RADS score they assigned to it.

Probability of Malignancy (POM): POM is a 0 to 100 score assigned by

readers to each suspicious finding, as their perception of the percentage
chance that the suspicious finding might be malignant. To help the assignment
of POM scores, readers were instructed to use the entire POM scale, with
descriptions of POM values provided below as guidance:
Note: POM scores were determined and analyzed separately from the BI-
RADS score.

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 20

 Table 8. Probability of malignancy (POM) guidance
POM Score (%) Description
0-20 Negative/Benign
21–40 Probably benign
41–60 Possibly malignant
61–80 Probably malignant
81–100 Malignant

Statistical Methods for Primary Analysis

The primary endpoint, AUC, was estimated for each reader in each review
condition (FFDM, FFDM + DBT) based on per-subject POM scores requiring
correct lesion localization.

Primary analysis did not involve pooling across study radiologists, to allow for
heterogeneity across them. Rather, each reader’s empirical ROC curve were
averaged to yield the overall comparison. For each reader, the non-parametric
(trapezoidal) AUC for the FFDM read, the FFDM + DBT read, the difference
between them, and the associated variance-covariance matrix were obtained using
the method of DeLong, et al.1 Statistical inferences accounted for correlations
arising from having all study readers interpret same study cases. MRMC
comparison of AUCs between the FFDM read and the FFDM + DBT read was
performed using the mixed effects analysis of variance (ANOVA) method of
Obuchowski and Rockette2 with degrees of freedom updated as in Hillis.3 Two-
sided 95% confidence intervals (CIs) were used to quantify uncertainty.

Successful demonstration of the safety and effectiveness of the ASPIRE Cristalle

DBT Option (Fujifilm DBT system) is defined as the average of per-subject AUC
for FFDM + DBT being statistically significantly superior to the average AUC for
FFDM at statistical significance level alpha = 0.05, which is established if the
lower limit of the two-sided 95% CI for the difference in average AUC for FFDM
+ DBT minus FFDM lies entirely above zero (0).

Supportive analysis. Alternative free-response receiver operating characteristic

(AFROC) curves, based on multiple reader findings per case, were used in
supportive analysis of the primary aim.6 MRMC jackknife AFROC (JAFROC)
analysis employing the Dorfman, Berbaum, and Metz4 method with Hillis
updates,5 and the weighted JAFROC (wJAFROC) figure of merit (FOM) with
equal weight assigned to all malignant lesions within a cancer case, was
performed. This analysis takes into account the correlations arising from having
all study readers interpret all study cases.

Missing data: One-year follow-up. Primary analysis of AUC classified 37 of

the 71 recall cases and 35 of the 119 negative cases without one-year negative
follow-up as non-cancer cases, consistent with an interval cancer rate of 0.77 per
1000 screening exams and an expected number of interval cancers among these
cases equal to 0.15.8 A sensitivity analysis was performed to explore robustness of
the results by re-classifying some of the recall and negative cases missing one-

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 21

 year follow-up as cancer in a “worst case” AUC analysis. Plausible cancer rates
(4.91 cancers per 1000 as an upper bound) and a predefined threshold on
probability of number of cancers (0.001) were used to determine that at most 3
cases without negative one-year follow-up should be reclassified in the robustness
analysis. These cases were selected as the ones with the lowest average POM
scores for FFDM + DBT (worst case if these were actually cancer) across readers.
The results of this analysis supported the robustness of the conclusions of the
primary analysis.

Adverse Event
The analysis of safety was based on the 1232 enrolled subjects as of December
30, 2015. There was only one adverse event reported during the image
acquisition study. One subject fainted during her study procedure. The enrolling
center determined that the event was not related to the study procedure nor the
investigational device. The subject fully recovered before leaving the clinical
center

D. Safety and Effectiveness Results

1. Safety Results
The analysis of safety was based on the 1216 enrolled patients as of December 31,
2016. There was only one adverse event reported during the image acquisition
study. One subject fainted during her study procedure. It was determined by the
enrolling center not to be related to the study procedure or investigational device.

Average Glandular Dose: With the addition of the DBT images to the standard
FFDM screening procedure, the radiation dose delivered to the patient increases.
Physical laboratory testing of DBT radiation dose (ST mode, N-dose) for a
standard breast (42 mm, 50% fibroglandular tissue, 50% adipose tissue) for one
view equals 1.2 mGy, and the dose for a standard breast, for one view FFDM is
0.75 mGy. (K133972).

An evaluation of the average glandular dose per view was performed using the
298 subject pivotal study case cohort. Results from this evaluation are provided
below.

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 22

 Average Glandular Dose (AGD) per View (DBT)
6

5
AGD/View (mGy)
4

0
0-39mm 40-49mm 50-59mm 60-69mm 70+ mm
N=41 N=62 N=93 N=72 N=30
Breast Thickness

Figure 4. Average Glandular Dose, DBT only, per view, stratified by breast
thickness, in the 298 patients enrolled in the pivotal MRMC study.

2. Effectiveness Results
The analysis of effectiveness was based on the 298 evaluable patients. The
primary endpoint for the study was met. The pivotal study showed that
radiologists had superior per-subject average area under the receiver operating
characteristic (ROC) curve (AUC) for FFDM + DBT, 0.837, versus FFDM,
0.784. The increase in average AUC was 0.053 (two-sided 95% CI: 0.028, 0.078;
p < 0.01). Analysis of alternative free-response operating characteristic (AFROC)
curves which allow multiple reader findings per case, and worst-case analysis re-
classifying some recall and negative cases without one-year negative follow-up as
cancer cases, support the robustness of this conclusion.

The average empirical ROC plot across readers for FFDM + DBT is entirely
above the average for FFDM (Figure 5).

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 23

 Figure 5. Average of Empirical ROC Plots for FFDM and FFDM + DBT.

Supportive analysis: JAFROC. Alternative free-response receiver operating

characteristic (AFROC) curves, which allow multiple reader findings per case, were
used in supportive analysis of the primary aim (Figure 6).6 Radiologists had superior
AFROC figures of merit (FOMs) for FFDM + DBT, 0.813, versus FFDM, 0.763.
The increase in average FOM was 0.050. Therefore, the results for the primary
endpoint can be considered to be robust to deriving, from one or more reader
findings, a single score per case requiring correct lesion localization.

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 24

 Figure 6. Average of Empirical AFROC Plots for FFDM and FFDM + DBT.

Supportive analysis: Missing one-year follow-up. Primary analysis of AUC

classified recall and negative cases without one-year negative follow-up as non-
cancer cases. A “worst case” AUC analysis was performed exploring robustness of
the results to this classification decision. Using plausible cancer rates during follow-
up we obtained 3 as the number of cases to be re-classified as cancer. The estimated
increase in AUC for FFDM + DBT versus FFDM in the worst-case analysis was
0.049. We therefore consider the results of AUC analysis to be robust to classifying
as non-cancer cases the 72 out of 190 recall and negative cases that are missing one-
year negative follow-up

3. Secondary Endpoints
The following preoperative characteristics were evaluated for potential
association with outcomes: recall rate for non-cancer cases, sensitivity, recall rate
for cancer cases, specificity.

The study’s type I error rate at alpha = 0.05 was controlled by performing
hypothesis testing hierarchically in the pre-specified fixed sequence. Recall rate
PMA P160031: FDA Summary of Safety and Effectiveness Data Page 25
 for non-cancer cases (secondary endpoint 1): Radiologists had superior (lower)
recall rate in non-cancer cases for FFDM + DBT, 0.262, versus FFDM, 0.362.
The decrease in average recall rate was 0.100 (two-sided 95% CI: 0.066, 0.134; p
< 0.01). Recall rate was analyzed using the yes or no answer to the separate
Recall question.

Per-subject sensitivity (secondary endpoint 2): Radiologists had non-inferior per-

subject sensitivity for FFDM + DBT versus FFDM. The increase in average per-
subject sensitivity was 0.116 (two-sided 95% CI: 0.071, 0.161; non inferiority p <
0.01 for non-inferiority margin delta = 0.05). Analysis of sensitivity was based on
forced BI-RADS scores requiring correct lesion localization, with BI-RADS 4 or
5 considered a positive test (true positive, TP).

Recall rate for cancer cases (secondary endpoint 3): Radiologists had non-inferior
recall rate for cancer cases for FFDM + DBT, 0.771, versus for FFDM, 0.740.
The increase in average recall rate for cancer cases was 0.031 (two-sided 95% CI:
-0.004, 0.066; non-inferiority p < 0.01 for non-inferiority margin delta = 0.05).
Recall rate was analyzed using the yes or no answer to the separate Recall
question, requiring correct lesion localization in these cancer cases.

Per-subject specificity (secondary endpoint 4): Radiologists did not have high
per-subject specificity. Analysis of specificity was based on forced BI-RADS
scores, with BI-RADS 1, 2 or 3 considered a negative test (true negative, TN).
Average specificity was less for FFDM+DBT compared to FFDM alone (0.878
for FFDM + DBT and 0.897 for FFDM; two-sided 95% CI of difference in
specificity: -0.039, 0.001).

4. Pediatric Extrapolation
In this premarket application, existing clinical data was not leveraged to support
approval of a pediatric patient population.

A. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires
applicants who submit a marketing application to include certain information
concerning the compensation to, and financial interests and arrangement of, any
clinical investigator conducting clinical studies covered by the regulation. The
clinical research studies included the following radiologists, for which none of the
clinical investigators or radiologists had disclosable financial
interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The
information provided does not raise any questions about the reliability of the data.
• image acquisition study
o one primary investigator
o Six principal investigators, and
o 20 sub-investigators
• pilot studies: 16 radiologists

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 26

 • pivotal study 28 radiologists
• one truthing radiologist
• one training radiologist

XI. PANEL MEETING RECOMMENDATION AND FDA’S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe
Medical Devices Act of 1990, this PMA was not referred to the Radiological Device
Panel, an FDA advisory committee, for review and recommendation because the
information in the PMA substantially duplicates information previously reviewed by this
panel.

XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

A. Effectiveness Conclusions

The multiple-reader multiple-case (MRMC) study showed that when two-view

DBT (MLO and CC), acquired with the ASPIRE Cristalle DBT option, is used as
an adjunct to FFDM images reader performance on average increases 0.053 AUC
ROC units with two-sided 95% CI: 0.028, 0.078; p < 0.01.

Combined with physical laboratory test results and sample image evaluation, the
pivotal study results demonstrate that the ASPIRE Cristalle DBT option used as an
adjunct is superior to FFDM alone.

B. Safety Conclusions

The risks of the device are based on physical laboratory testing as well as data
collected in a clinical study conducted to support PMA approval as described above.
The risk of direct harm to the patient is minimal. There was one adverse event
during the collection study, but this event was not related to the proposed device.

The risk posed by the proposed device is similar to that of other screening and
diagnostic mammography devices.

C. Benefit-Risk Determination

The probable benefits of the device are based on data collected in a clinical study
conducted to support PMA approval as described above.

The ASPIRE Cristalle DBT option is used to reconstruct the breast volume from
limited angle projections while reducing the tissue overlapping effect observed in
two-dimensional projections. It is likely to benefit a substantial number of screening
patients whose cancers could have otherwise been missed due to tissue

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 27

 superimposition (false negatives), or who may otherwise have been unnecessarily
referred for additional workup (false positives).

The proposed device has no significant risk of direct harm to the patient.
The primary risk of the device comes from the possibility of false positive and false
negative clinical decisions when using the images produced by the ASPIRE Cristalle
DBT option. The applicant conducted an MRMC study to compare the performance
of readers with FFDM alone and with FFDM plus two-view DBT. The study design
is consistent with other mammography studies. Because MRMC studies are
conducted outside some clinical norms (with an enriched case set, and without
patient history), the generalizability of some figures of merit such as recall rate,
sensitivity and specificity is limited. Nonetheless, the design is considered
acceptable in order to reduce the size of the trial and avoid confounders.

Adding two-view DBT as an adjunct to FFDM requires additional exposure to

ionizing radiation. Overall, the FFDM plus two-view DBT mammography exam
remains a low dose examination. The risk associated with exposure to low dose
radiation is theoretical and long-term, while an undetected breast cancer, particularly
of the invasive type, is an immediate risk to a patient.

Additional factors to be considered in determining probable risks and benefits for the
ASPIRE Cristalle DBT option included two study design choices that added some
uncertainty to the estimated difference of reader performance between FFDM and
FFDM plus two-view DBT. These were the method used to assign a POM score to a
case by combining the lesion level scores and the classification of subjects without
negative one-year follow-up as non-cancer. Supportive analyses indicate that the
impact of these design choices is unlikely to be large enough to alter the study
conclusions.

Patient Perspective:
This submission did not include specific information on patient perspectives for
this device.

In conclusion, given the available information described above, the data support that
the probable benefits of using the ASPIRE Cristalle DBT option as an adjunct to
FFDM (in accordance with the indications for use) outweigh the probable risks.

D. Overall Conclusions

The data in this application support the reasonable assurance of safety and
effectiveness of the ASPIRE Cristalle DBT option when used in accordance with the
indications for use.

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 28

XIII. CDRH DECISION

CDRH issued an approval order on January 10, 2017.

The applicant’s manufacturing facilities have been inspected and found to be in

compliance with the device Quality System (QS) regulation (21 CFR 820).

XIV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling.

Hazards to Health from Use of the Device: See Indications, Contraindications,

Warnings, Precautions, and Adverse Events in the device labeling.

Post-approval Requirements and Restrictions: See approval order.

PMA P160031: FDA Summary of Safety and Effectiveness Data Page 29