FDA Executive Summary

Transcription

1 Meeting of the Radiological Devices Advisory Panel On October 24, 22, the panel will discuss, make recommendations, and vote on a premarket approval application supplement (P83/S) to expand the indications for use of the Selenia Dimensions 3D System with C-View Software Module, sponsored by Hologic, Inc. The Selenia Dimensions 3D System is currently approved (PMA-number: P83) for breast cancer screening and diagnosis. The screening exam can consist of full field digital mammography (FFDM) alone or the combination of FFDM with digital breast tomosynthesis (DBT). The new C-View Software Module can generate synthesized 2D images from the DBT data. Hologic would like to expand the indications for use to allow the combination of DBT with synthesized 2D images to be used as another exam option for breast cancer screening. Federal Notice Panel Date and Location October 24, 22 from 8 AM to 6 PM Hilton Washington DC North/Gaithersburg 62 Perry Pkwy., Gaithersburg, MD 2877 Contact Person Shanika Craig Food and Drug Administration Center for Devices and Radiological Health 93 New Hampshire Ave., Building 66, Room 63 Silver Spring, MD

2 Table of Contents Section Page Number Introduction... 3 I. Rationale for Presentation to the Panel... 4 II. Background Information... 5 A. Indications for Use... 5 B. Device Description... 5 C. Non-clinical Testing... 6 III. Reader Study... 7 A. Overview... 7 B. Subjects... 8 C. Reference Standard... D. Readers... E. Image Scoring... F. Primary Endpoint ROC Analysis...2 G. Secondary Endpoints (Dense Breasts)...8 H. Secondary Endpoint (Non-cancer Recall Rate)...9 I. Additional Analysis...2 IV. DISCUSSION...26 A. Potential Impact on Screening Mammography...26 B. Study design...27 C. Study Population...28 D. Safety...29 E. Effectiveness...29 F. Benefit / Risk...29 V. Panel Questions...32 A. Questions for Panel Discussion...32 B. Questions for Ballot Vote...33 Page 2 of 33

3 Introduction Hologic, Inc. has submitted a premarket approval application supplement (P83/S) to expand the indications for use of the Selenia Dimensions 3D System with C-View Software Module. The Selenia Dimensions 3D System is currently approved for the acquisition of both conventional full field digital mammography (FFDM) and 3D digital breast tomosynthesis (DBT) images. The device is intended for use in the same clinical applications as full field digital mammography (FFDM); the screening exam can consist of FFDM alone or the combination of FFDM with DBT. The C-View Software Module will be a new addition to the Selenia Dimensions 3D System to generate synthesized 2D images from the DBT data. Hologic would like to indicate the combination of DBT with synthesized 2D images (3D s ) as a new exam option for breast cancer screening. With this new combination, the synthesized 2D images would essentially be an alternative to acquiring FFDM images. The design of the Selenia Dimensions 3D System is otherwise unchanged since approval. The device will still offer the capability of acquiring FFDM images alone, or FFDM plus DBT images. Hologic has submitted the results of a pivotal multi-reader, multi-case study to demonstrate that the combination of DBT with synthesized 2D images is non-inferior to the standard of care FFDM for breast cancer screening. Table : Summary of the abbreviations used in the executive summary. Abbreviation Explanation Images (per breast) FFDM Full Field Digital Mammography (FFDM) conventional mammography 2-view FFDM (MLO and CC) DBT Digital Breast Tomosynthesis Images 2-view DBT (MLO and CC) 3D s Synthesized 2D Tomosynthesis 3D images plus Synthesized 2D images 2D images(s) created from the tomosynthesis (3D) images. Similar to CT scout views, or maximum intensity projections. Requires no additional radiation dose (as it is created from the acquired 3D data). This executive summary includes four sections:. Summary of the issues for panel discussion; 2. Summary of the Indications for Use and device description; 3. Review of the clinical reader study; and 4. Questions for panel discussion and voting. 2-view DBT (MLO and CC), and 2-synthesized views (MLO and CC) 2-synthesized views (MLO and CC) Page 3 of 33

4 I. Rationale for Presentation to the Panel FDA seeks advice from the Radiological Devices Panel on the Hologic s proposal to expand the Indications for Use of their digital breast tomosynthesis system to indicate the combination of DBT with synthesized 2D images as a new exam option for breast cancer screening. The new 3D s option will impact how mammography is performed since FFDM images will not be acquired. Currently, FFDM is the standard of care for breast cancer screening, and DBT was originally approved for the use with FFDM. While the synthesized 2D images are intended to resemble the FFDM images, Hologic is not claiming that the synthesized images are equivalent to FFDM images. The image quality of the synthesized 2D images alone was not directly compared to FFDM. The study design reflects the indication for the synthesized 2D images to be used with DBT. FDA would like the panel to discuss the potential impact of using only DBT plus synthesized 2D images clinically. While the MRMC study design can evaluate the diagnostic effectiveness of the new exam option, FDA would like to know if there are other labeling or training recommendations to consider when the standard of care FFDM images are not available. The panel is also asked to consider other aspects of the study design, patient population, safety, effectiveness, and benefit/risk when reviewing this submission. Page 4 of 33

5 II. Background Information A. Indications for Use Currently Approved (P83) The Hologic Selenia Dimensions System generates digital mammographic images that can be used for screening and diagnosis of breast cancer. The Selenia Dimensions (2D or 3D) system is intended for use in the same clinical applications as 2D mammography systems for screening mammograms. Specifically, the Selenia Dimensions system can be used to acquire 2D digital mammograms and 3D mammograms. The screening examination will consist of a 2D image set or a 2D and 3D image set. The Selenia Dimensions system may also be used for additional diagnostic workup of the breast. The Hologic Selenia Dimensions system generates digital mammographic images that can be used for screening and diagnosis of breast cancer. The Selenia Dimensions (2D or 3D) system is intended for use in the same clinical Proposed applications as a 2D mammography system for screening mammograms. Modification Specifically, the Selenia Dimensions system can be used to acquire 2D digital mammograms and 3D mammograms. Each view in a screening examination will (P83/S consist of: ) a 2D image set, or a 2D and 3D image set, or a 3D image set in combination with a synthesized 2D image set The Selenia Dimensions system may also be used for additional diagnostic workup of the breast. Note: In the Indications for Use, 2D image set refers to conventional 2D FFDM and 3D refers to DBT. Hologic requests approval to expand the Indications for Use to include the combination of DBT with synthesized 2D images (3D s ) as alternative exam options for breast cancer screening. B. Device Description The Selenia Dimensions 3D System (P83) is a hardware and software upgrade to the Selenia Dimensions 2D FFDM system, which was FDA approved for conventional mammography imaging (P25/S3, approved December 22, 28). To acquire the 3D DBT images, the x-ray tube head is moved in a 5 o arc over the stationary breast acquiring 5 low dose x-ray projection images. The projection images are reconstructed to produce cross-sectional slices through the breast. The same detector and x-ray tube is used to acquire both the 2D and 3D images. Images can be acquired in any orientation of the gantry, including the standard CC and MLO mammography views. The 2D and 3D images can be acquired during a single breast compression, or they can be acquired separately. The C-View Software Module (P83/S) generates a synthesized 2D image from the tomosynthesis images, offering an alternate method of utilizing tomosynthesis in a screening exam. The synthesized 2D image is essentially a maximum intensity projection created from collapsing the 3D image set to a single 2D image. The synthesized 2D images can be displayed together with the 3D tomosynthesis images. Page 5 of 33

6 The synthesized 2D images will have C-View incorporated into the pixel data to alert users that they are not FFDM images. The 3D DBT images and synthesized 2D images are generated from the single DBT acquisition, thus eliminating the radiation exposure from the 2D FFDM acquisition. The single acquisition also reduces the total time of breast compression. System configurations allow adjustments to two aspects of the synthesized 2D images. The default contrast of the overall image can be set to low, medium, or high (window level setting on the review workstation are still adjustable). The appearance of the skin line can be set as less prominent or more prominent. The configurations can only be adjusted by a Hologic Service Engineer. The medium contrast and more prominent skin line were used for the images in the reader study. The impact of different configurations was not evaluated. The radiation exposure to a standard phantom for a single DBT acquisition is.45 mgy, which is higher than the.2 mgy exposure for a single FFDM acquisition to the same phantom. The average glandular dose measured for the subjects imaged in the Hologic study was.86 mgy per view for FFDM and 2.25 mgy per view for DBT. The difference between the phantom dose and average subject dose primarily reflects that the average compressed breast thickness of the subjects in the study was higher than the 4.2 cm simulated compressed breast thickness used for the phantom. C. Non-clinical Testing The addition of the C-View Software Module does not impact the image quality or performance of the FFDM or DBT systems. The design is otherwise unchanged since the approval of the Selenia Dimensions 3D Systems (P83). The sponsor provided design and test documentation to support that the C-View Software Module can be successfully integrated into the Selenia Dimensions 3D System. Page 6 of 33

7 III. Reader Study Hologic submitted the results of a reader study to support the addition of the C-View Software Module and change to the Indications for Use statement. A. Overview INTENDED USE STUDY OBJECTIVE The screening examination will consist of [ ] a 3D image set in combination with a synthesized 2D image set. To compare the performance of 3D tomosynthesis plus synthesized 2D images (3D s) to the use of conventional 2D FFDM images alone. 2D FFDM (CC & MLO views) vs. 3D DBT (CC & MLO views) plus synthesized 2D views (CC & MLO views) 32 Subjects were randomized / selected into reader study; subjects were from either a screening group or a biopsy group. The cases were not previously used in any of Hologic s prior pilot or pivotal reader studies. SUBJECTS REFERENCE STANDARD IMAGES READERS Distribution of cases: 77 Cancers 24 Recalled Screening Cases 75 Benign Biopsy 26 Screening Negatives Negative screening cases: negative on clinical FFDM images and investigational FFDM plus DBT images at acquisition site (BI-RADS or 2 score considered negative) Recalled screening cases: recalled on clinical FFDM images or investigational FFDM plus DBT images at acquisition site; determined to be non-cancer with additional follow-up (does not included benign biopsy cases) Benign biopsy cases: pathology proven benign cases Cancer cases: pathology proven malignant cases The FFDM and DBT images used in the reader study were acquired under a single compression (for each view) with a Selenia Dimensions investigational system. 5 Board certified and MQSA qualified radiologists; half of the readers had clinical experience with DBT READING SCHEDULE One month separation between the FFDM and DBT reading sessions. For each marked lesions: Lesion location (used for cancer recall rate analysis) Probability of Malignancy (POM) score of to IMAGE SCORING Forced BIRADS score of, 2, 3, 4a, 4b, 4c, or 5 For cases with no marked lesions: POM score of to BIRADS score of or 2 PRIMARY ENDPOINTS SECONDARY ENDPOINTS RADIATION EXPOSURE The ROC area under the curve (AUC) performance for 3D DBT plus synthesized 2D images (3D s) is non-inferior to that of 2D FFDM (a) ROC AUC for subjects with dense breasts using 3D s is non-inferior to that of 2D FFDM (b) The non-cancer recall rate for 3D s is non-inferior to that of 2D FFDM The radiation exposure for a single DBT view (.45 mgy) is approximately 2% higher than the radiation exposure for a single FFDM view (.2 mgy) as measured using a standard phantom. Page 7 of 33

8 B. Subjects Images and patient related information was obtained for 352 subjects from 22 collection sites. Subjects were enrolled from either a screening group or a biopsy group of women scheduled for biopsy. Inclusion Criteria Female No contraindication for routine bilateral mammography Exclusion Criteria Subjects who presented with any contraindications to mammographic screening, including, but not limited to: o Significant existing breast trauma o Pregnancy o Lactating Previous surgical (excisional) biopsy Previous breast cancer Placement of an internal breast marker Breast implants or breast reduction surgery Subjects who were unable to understand or execute written informed consent Breasts too large to be imaged on a 24 cm by 29 cm detector with a single exposure Subjects were imaged with an approved system to obtain the standard of care FFDM images. The FFDM and DBT images used in the reader study were acquired with a Selenia Dimensions investigational system. The FFDM and DBT views were acquired under the same compression to mitigate the confounding factor of different breast positioning. Figure indicates reasons for exclusions. Top reasons for excluding images at the site were: subject did not meet inclusion/exclusion criteria even though investigational imaging occurred (n=), investigation equipment failure (n=2), subject withdrew consent (n=6), biopsy procedure was cancelled after investigational imaging occurred (n=6), incomplete image set obtained (n=3). subjects were excluded because the images were obtained using the incorrect imaging technique tables. 9.8% (59/2985) of eligible cases were excluded for image quality control issues. The entire case was rejected and not used in the reader study if any of the FFDM or DBT images were rejected. The acquisition protocol did not allow for repeating any of the images. There were 3 FFDM images rejected and 7 DBT images rejected. The 32 cases used for the reader study were randomly selected using stratified sampling from the remaining 2299 cases. The dataset included 57 subjects from the screening cohort and 45 subjects from the biopsy group. The mean age of the 32 subjects was 54.2 years (range 24 to 84 years). The protocol required the collection of one year follow-up on all subjects. The 32 cases were randomized and used in the reader study before completing the collection of the one year follow-up on all cases. One year follow-up information was not available for 9 of the 32 Page 8 of 33

9 subjects (8 screening negatives; benign biopsy). One case was initially classified as a benign but was later diagnosed as a breast cancer within one year of study enrollment. Figure : Image Acquisition, Exclusions, and Eligible Subjects The follow tables report the distribution of cases by breast density, calcification/noncalcifications, and lesion size of invasive cancers based on the latest follow-up information. Table 2: Distribution of cases by breast density. BI-RADS Breast Cases (n=32) Density Category 37 (2.3%) 2 7 (38.7%) 3 8 (39.%) 4 3 (9.9%) Page 9 of 33

10 Table 3: Distribution of cases by calcifications/non-calcifications. Case Type Calcification Non-Calcification Total Cancer Recall Benign Negative Total Table 4: Distribution of size for invasive cancers. Cancer Type Mean Size (cm) Median Size (cm) Min (cm) Max (cm) Invasive (n=55) C. Reference Standard The following criteria was used to categorize cases: Negative screening cases: negative on clinical FFDM images and investigation FFDM plus DBT images at acquisition site (BI-RADS or 2 score considered negative) Recalled screening cases: recalled by clinical FFDM images or investigation FFDM plus DBT images at acquisition site; determined to be non-cancer with additional follow-up (does not included benign biopsy cases) Benign biopsy cases: pathology proven benign cases Cancer cases: pathology proven malignant cases The breast density score was performed at the acquisition site by two radiologists (with a third radiologists in the case of disagreement) using the standard of care FFDM images. Cases were categorized as either fatty (BI-RADS breast density type or 2) or dense (BI-RADS breast density type 3 or 4). D. Readers 5 Readers with a range of clinical and tomosynthesis experience participated in the study. Readers were board certified and MQSA qualified. Readers were given two full days of training on the reading of 3D tomosynthesis with synthesized 2D images prior to the start of the reader study. To be included in the reader study, readers had to complete all of the reader training and pass a final assessment with an independent set of cases. The pre-specified initial criteria would have excluded 6 of 5 readers for a high recall rate on FFDM. Hologic redefined the criteria to exclude readers beyond a.65 standard deviation mean of all readers. This would have resulted in 2 study readers (one reader excluded for cancer detection based on both FFDM and DBT performance; one reader was excluded for a high FFDM recall rate; and one reader was excluded for a high DBT recall rate). Hologic stated the redefinition of the pass criteria was performed prior to the analysis of the results. Page of 33

11 FDA requested that the statistical analysis be performed with all 5 subjects to avoid a bias of selecting the only best FFDM and/or DBT readers either for the study. The 5 readers were all board certified and MQSA qualified and would reflect the intended users. The assessment test and pass threshold would not reflect criteria that would be applied to potential clinical users. E. Image Scoring This was a crossed reader study design. In Session, the readers scored half of the cases with FFDM and half of the cases with the combination of DBT and synthesized 2D image. In session 2, the readers scored each case using the other exam option. The synthesized 2D images were provided to the reader when the corresponding DBT images were viewed. The following information was collected for each marked lesion: Lesion location (used for cancer recall rate analysis) Probability of Malignancy (POM) score of to Forced BI-RADS score of, 2, 3, 4a, 4b, 4c, or 5 The following information was collected for cases with no marked lesions: POM score of to BI-RADS score of or 2 The ROC and non-cancer recall analysis relied on case based scoring. For the non-cancer recall rate analysis, any case with a lesion marked was considered a recall (BI-RADS ). For cases with multiple lesions, the lesion with the highest POM score was used as the POM score for the case. The cancer recall rate used lesion based scoring. When reviewing the combination of the DBT and synthesized 2D images, the lesion location was recorded on the slice of the DBT image that determined to be at the center of the lesion. Page of 33

12 F. Primary Endpoint ROC Analysis The primary endpoint evaluated whether the ROC area under the curve (AUC) performance for 3D DBT plus synthesized 2D images (3D s ) is non-inferior to that of FFDM. The non-inferior margin was pre-specified: 3D s is considered non-inferior to FFDM if the lower limit one-sided 95% CI for the difference in AUCs (3D s - FFDM) is greater than -.5. The analysis was performed using DBM MRMC 2.3,2. The mean increase in the AUC was.4 (95% CI lower limit.4; p-value.5) (Table 5). The primary endpoint of noninferiority was met. The ROC AUC increased for 4 of the 5 readers; the AUC decreased by -.4 for one reader. Table 5: Difference in ROC AUC. ROC AUC Difference Reader 2D 3D s (3D s - FFDM) Mean p-value.5 95% lower CI.4 Dorfman, DD, Berbaum, KS, Metz, CE. Receiver operating characteristic rating analysis: Generalization to the population of readers and patients with the jackknife method. Investigative Radiology 992:27: Hillis, SL, Berbaum, K.S., Metz, C.E. Recent developments in the Dorfman-Berbaum-Metz procedure for multireader ROC study analysis. Academic Radiology 28:5: Page 2 of 33

13 The average of the ROC curves for the readers is presented in Figure 2. The curves were created by averaging the sensitivity of the individual readers ROC curves across specificity. FDA notes that pooling reader scores to compute a pooled curve can result in a curve that appears reduced when compared to the individual reader curves. Figure 2: Mean ROC curves for readers. The empirical curves were calculated by FDA and are overlaid onto the parametric curves calculated by Hologic. Page 3 of 33

14 Figure 3: FDA calculated individual parametric ROC curves along with the observed operating points in terms of POM, Recall BI-RADS (: recall), and forced BI-RADS (3, 4a, 4b, 4c, and 5: positive). Reader # Reader #2. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS.. Reader #3 Reader #4. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS.. Page 4 of 33

15 Reader #5 Reader #6. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS.. Reader #7 Reader #8. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS.. Page 5 of 33

16 Reader #9 Reader #. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS.. Reader # Reader #2. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS.. Page 6 of 33

17 Reader #3 Reader #4. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS.. Reader #5. 3Ds - observed 3Ds - Fitted FFDM - observed FFDM - Fitted 3Ds - Recall FFDM - Recall 3Ds - Forced BIRADS FFDM - Forced BIRADS. Page 7 of 33

18 G. Secondary Endpoints (Dense Breasts) The secondary endpoint for breast density was to show that the ROC AUC for subjects with dense breasts using 3D s is non-inferior to that of FFDM. The non-inferiority margin was prespecified: 3D s is considered non-inferior to FFDM in dense breasts if the lower limit one-sided 95% CI for the difference in AUCs (3D s - FFDM) is greater than -.5. The mean increase in AUC was.45 (95% CI lower limit.6; p-value.27) (Table 6). The non-inferiority endpoint was met. The AUC increased for 4 of 5 readers; the AUC decreased by -.9 for one reader. Table 6: Difference in ROC AUC for subjects with dense breasts (BI-RADS breast density type 3,4). ROC AUC Difference Reader 2D 3D s (3D s - FFDM) Mean p-value.27 95% lower CI.6 Page 8 of 33

19 H. Secondary Endpoint (Non-cancer Recall Rate) The secondary endpoint for recall rate was to demonstrate that the non-cancer recall rate for 3D s is non-inferior to that of FFDM. The non-inferiority margin was pre-specified: If the upper limit to the one-sided 95% confidence interval for the difference (3D s - FFDM) in recall rates among non-cancers is less than.5, then 3D s is considered non-inferior to FFDM. Bootstrapping with replacement was used to obtain average estimates of the recall rate. The bootstrap samples are based on pairs of reads (the FFDM read and the 3D s read) to preserve the correlation structure from the original experiment and to maintain the ratio of cases in each group benign/negative/recall. The non-cancer recall rate decreased for all 5 readers (Table 7). The average difference was - 3.9%, with the one-sided 95% CI upper limit of -.%. The non-inferiority endpoint was met. The reduction in recall rate was consistent across the stratifications of screening negatives, screening recalls, and benign cases (Table 8). Table 7: Bootstrap estimate of non-cancer recall rate. Reader 2D Recall Rate 3D s Recall Rate Difference: 3D s - 2D One-sided 95% CI Upper Limit 43.5% 36.5% -7.% -.% % 37.3% -3.4% -25.8% % 23.5% -.6% -6.7% % 7.9% -9.3% -4.9% 5 3.2% 23.6% -7.6% -2.7% % 3% -9.2% -2.9% % 36.9% -8.3% -2.9% % 27.7% -9.2% -3.6% 9 5.% 33.8% -7.3% -2.% 5.7% 42.2% -9.5% -4.4% 52.8% 38.7% -4.% -8.% % 33.5% -4.2% -8.4% % 22.3% -6.% -% % 42.8% -.% -4.% % 35.% -2.4% -7.% All 46.% 32.% -3.9% -.% Page 9 of 33

20 Table 8: Mean difference in recall rates stratified by non-cancer categories for all readers. Mode Negative Screening Recall Screening Benign (N=26) (N=24) (N=76) 2D Recall Rate 32.7% 49.4% 67.% 3Ds Recall Rate 7.4% 38.9% 54.8% Difference (3D s 2D) -5.3% -% -2.3% I. Additional Analysis Breast Density: Table 9 and Figure 4 present the ROC analysis stratified by subjects with fatty and dense breasts. The results indicate an improvement in ROC AUC with 3D s for both stratifications. The increase with 3D s was greater for subjects with dense breasts. Table 9: ROC analysis stratified by fatty (BI-RADS breast density type,2) and dense (BI- RADS breast density type 3,4) breasts. Sub-population FFDM ROC AUC 3D s Difference (3D s FFDM) 95% CI Lower Limit p-value Dense Breasts (n=48) Fatty Breasts (n=54) Figure 4: Mean ROC curves of all readers stratified by breast density. Dense 3Ds All Readers 2D.. Fatty 3Ds. All Readers 2D. Page 2 of 33

21 Lesion Type (calcification and non-calcification): Table and Figure 5 present the ROC analysis stratified by cases with calcifications and non-calcification lesions. The ROC AUC results indicate that 3D s is non-inferior for both stratifications. Table : ROC analysis stratified by cases with calcifications and non-calcification lesions. Sub-population FFDM ROC AUC 3D s Difference (3D s FFDM) 95% CI Lower Limit p-value Calcifications (n=56) Non-calcifications (n=246) Figure 5: Mean ROC curves of all readers stratified by cases with calcification and noncalcification lesions. Calcification 3Ds. All Readers 2D. Non-calcification 3Ds. All Readers 2D. Sensitivity and Specificity: Table summarizes the mean sensitivity and specificity values for all readers using BI-RADS 4a, 4b, 4c, or 5 as positive. The results for individual readers are presented in Table 2 and Figure 6. Similar trends in sensitivity and specificity were seen when using BI-RADS 3 (not included with this summary) or BI-RADS 4a as the positive cut points. The largest change was a decrease in specificity with 3D s. Table : Sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) using BIRADS 4a, 4b, 4c, or 5 as positive. FFDM 3D s Difference (3D s FFDM) Sensitivity 86.2% 86.8% % Specificity 65.% 75.% 9.9% Specificity (screening cases) 74.5% 84.8% % Positive Likelihood Ratio Negative Likelihood Ratio -.4 Page 2 of 33

22 Table 2: Individual reader sensitivity and specificity using BIRADS 4a, 4b, 4c, or 5 as positive. Sensitivity Specificity Reader FFDM 3D s FFDM 3D s 83.% 8.8% 72.% 73.3% 2 96.% 9% 52.% 72.9% % 84.4% 7.% 84.9% % 85.7% 84.9% 9.% 5 8% 83.% 74.2% 8.8% % 87.% 68.4% 78.2% % 85.7% 49.3% 7% 8 8% 85.7% 82.7% 82.7% % 87.% 53.8% 69.8% 94.8% 9% 48.4% 57.8% 87.% 92.2% 57.8% 68.9% % 8% 79.% 83.6% 3 8.8% 85.7% 6.8% 77.8% % 92.2% 6% 66.2% % 89.6% 6.% 65.8% Figure 6: FDA calculated change individual reader sensitivity and specificity from FFDM to 3D s using BIRADS 4a, 4b, 4c, or 5 as positive. Page 22 of 33

23 Cancer Recall Rate: The ROC and non-cancer recall analysis used case based scoring rather than lesion based scoring. The cancer recall rate was measured with a requirement that the readers correctly identified the lesion location and lesion type (calcification versus noncalcification). The cancer recall rate increased from 82.3% with FFDM to 85.3% with 3D s. The results support that the ability of the readers to accurately identify the lesion location and type is the same or better with 3D s compared with FFDM. Reader Experience: The volume of mammography exams read by the individual study readers ranged from 9 to exams per year. A across stratifications of reader experience, the results indicate an improvement in ROC AUC with the trend of greater improvement for the lower volume readers (Table 3). Table 3: ROC analysis stratified by volume of mammography exams read per year. Mammography Exams Read per Year Mean ROC AUC FFDM 3D s Mean Difference (3D s FFDM) Range of Difference (3D s FFDM) > 5 (n=5) to (n=6) to.68 3 (n=4) to.78 Tomosynthesis Experience: The study included readers with and without prior experience with tomosynthesis. Table 4 presents the ROC analysis stratified tomosynthesis experience. The results indicate an improvement in ROC AUC with 3D s for both groups of readers. Table 4: ROC analysis stratified by clinical experience with tomosynthesis. Tomosynthesis Experience Mean ROC AUC FFDM 3D s Mean Difference (3D s FFDM) Range of Difference (3D s FFDM) No (n=8) to.78 Yes (n=7) to.78 Readers: Hologic required that study readers to pass an assessment for their readings to be included in the pivotal study analysis. The initial pre-specified pass criteria would have excluded 7 readers, with 6 of the 7 readers being excluded for high FFDM recall rates on the assessment dataset. Hologic redefined the criteria to exclude readers beyond a.65 standard deviation mean of all readers. The new passing criteria would allow 2 study readers. The redefinition of the passing criteria was performed prior to the analysis of the results. FDA recommended that Hologic use all reader for the statistical analysis. Tables 5-7 summarize the primary and secondary endpoints stratified by the reader groups. When reviewing the tables of individual results (e.g., Table 5), the readers excluded by the pre- Page 23 of 33

24 specified criteria were readers 2,4,6,7,,3,4. The readers excluded by the redefined criteria were readers 2, 4, and 4. The mean difference in ROC AUC and non-cancer recall rate between FFDM and 3D s was consistent regardless of the reader group. Table 5: ROC AUC stratified by the reader groups. Individual reader performance is reported in Table 5. Reader Group Mean ROC AUC Mean Difference One sided 95% p-value 2D 3D s 3D s - 2D FFDM Lower Limit 8 Readers (who passed pre-specified criteria) Readers (who passed redefined criteria) All 5 Readers Table 6: ROC AUC stratified by the reader groups for dense breasts. Individual reader performance is reported in Table 6. Reader Group Mean ROC AUC Mean Difference One sided 95% 3D s - 2D FFDM p-value 2D 3D s Lower Limit 8 Readers (who passed pre-specified criteria) Readers (who passed redefined criteria) All 5 Readers Table 7: Bootstrapping estimate of the average non-cancer recall rates. Individual reader performance is reported in Table 7. Reader 2D Recall Rate 3D s Recall Rate Difference: 3D s - 2D One-sided 95% CI Upper Limit 8 Readers (who passed prespecified criteria) 43.% 3.4% -.7% -7.9% 2 Readers (who passed adjusted criteria) 45.% 32.% -3.% -9.6% All 5 Readers 46.% 32.% -3.9% -.% Page 24 of 33

25 Cases with missing follow-up: The statistical analysis was performed with all 5 readers and the reclassification of a benign case that was an interval cancer on follow-up. Of the 32 cases used for the reader study, 9 cases (8 negative and benign) were lost to follow-up; 5 of the 9 subjects had dense breasts. The analysis of the primary and secondary endpoints was also performed with the exclusion of the 9 subjects with missing follow-up. For all readers, the mean increase in the AUC was.4 (95% CI lower limit.5; p-value.5). For subjects with dense breasts, the mean increase in the AUC was.45 (95% CI lower limit.7; p-value.25). The non-cancer recall rate changed by -4.% (95% CI upper limit -%). Non-parametric Analysis: FDA performed a non-parametric analysis using DBM MRMC 2.2 for all 5 readers and excluding the 9 of 32 cases with missing one year follow-up information. The mean increase in the AUC was.38 (95% CI lower limit.3; p-value.6) (Table 8). The ROC AUC increased for 4 of the 5 readers; the AUC decreased by -.9 for one reader. The results are consistent with the parametric DBM MRMC results used for the primary analysis (Table 5). Table 8: Difference in empirical ROC AUC. ROC AUC Difference Reader 2D 3D s (3D s - FFDM) Mean p-value.6 95% lower CI.3 Page 25 of 33

26 IV. DISCUSSION The following section reflects topics FDA would like the panel to consider during the discussion and vote sessions. These issues are considered most relevant to the device approval. A. Potential Impact on Screening Mammography FFDM will not be acquired under the proposed 3D plus synthesized 2D images (3D s ) exam option. Since FFDM is part of the current standard of care for breast cancer screening, this will impact how mammography is performed. The objective of the reader study was to compare the new 3D s exam option against the current standard of care. While the overall design is considered acceptable, FDA also recognizes that the study may not have fully evaluated other aspects of using the 3D s images for performing mammography. For example, FFDM images acquired during the current exam are used for comparison with images acquired during prior exams. Since the patient history and prior images were not available to study readers, the use of the 3D s images for this task was not covered in the reader study. Hologic did not demonstrate that the synthesized 2D images alone are equivalent to FFDM. The results support the use of 3D s, but users should also be aware that the synthesized 2D images should only be used in combination with the 3D tomosynthesis data when reviewing prior exams. The synthesized 2D images will contain a C-View mark so users will know they are not FFDM images. The C-View User Instructions also include warning statements to alert users that the C- View images should be used as an aid while examining the tomosynthesis images, and that users should not make a clinical decision or diagnosis from the C-View images alone. Training will also be important for new users. To participate in the study, the radiologists were required to go through two full day training sessions, including an evaluation session. The training samples included approximately 5 cases. The reader assessment was performed with an additional set of cases. These cases consisted of approximately one-third cancer cases, one third recalled or superimposed tissue cases, and a mixture of benign biopsy and negative screening cases. The focus of the training was on the task of the reader study and may not have covered other aspects of using the 3D s when performing mammography. Panel recommendations may help in the design of the training programs for clinical users. Panel Discussion: FDA would like the panel to discuss aspects of performing mammography that should be considered in the training and/or labeling when FFDM are not acquired during the screening exam. Page 26 of 33

27 B. Study design Because a prospective study is prohibitive due to low prevalence of cancer, a retrospective study was conducted and enriched with cancer cases. The study had the following limitations, which might affect the generalizability of the results to the intended population: Radiologists are reading images knowing that their readings do not affect patient management. Radiologists are scoring the image without the use of prior images or clinical history. Radiologists know or will learn that the case set is highly enriched with cancer cases. The study was enriched with recalls and cancer cases that were identified based on standard FFDM imaging. This may have been bias the study in favor of the FFDM mode because the selection cancer cases may have excluded cases that were missed on the initial FFDM review, but might have otherwise been recalled with the use of DBT. Statistically, there may be ways to account for this bias, but some of the new techniques may still need to be validated on a clinical dataset. Compared to the study population used for the original PMA, the proportion of recall cases was reduced and the proportion of cancer patients was increased. This was done to avoid a bias in favor of DBT, since many of the negative cases recalled on FFDM would not have been recalled on DBT. The reduction in recalls and increase in cancers may have also made the task of differentiating cancers from non-cancers easier. The ROC AUC is likely to be higher when asking readers to differentiate (screening negatives vs. cancers) compared with asking reader to differentiate (recalls vs. cancers). The use of an easier dataset could have favored the 3D s for a non-inferiority endpoint since both devices would likely perform well. 9.8% (59/2985) of eligible cases were excluded for quality control issues. The entire case was rejected and not used in the reader study if any of the FFDM or DBT images were rejected. The acquisition protocol did not allow for repeating any of the images. The performance on 3D and 2D could be different on cases that were excluded. In clinical practice, the subjects would most likely be reimaged. If reimaged (and images pass QC), these subjects could have been candidates for inclusion into the pivotal study. Many of the issues with the retrospective reader design are considered unavoidable. The study is retrospective and the readers know their actions will not impact the patient. Radiologists also do not have access to prior images or patient history, which could impact their scoring decision. While prospective studies would be ideal, they may be overly burdensome for each sponsor to undertake given the low prevalence of cancer. Panel Discussion: Does the panel have any specific concerns with respect to the study design or potential sources of bias? Page 27 of 33

28 C. Study Population The study protocol excluded subjects with previous surgical (excisional) biopsy, breast implants, and/or breasts too large to be imaged with a single exposure. The rationale for excluding subjects with previous surgical (excisional) biopsy from both studies was based on the reader study design. The protocol and study design did not allow for providing the readers with previous medical history or previous mammograms to review while reading the study acquired 2D and 3D images. In addition, the protocol did not allow scar markers to be placed on the patients during imaging, which does not reflect real world practice. The inclusion of this patient population could falsely increase the number of recalls in both the 2D and 3D s blinded reads, thus increasing the false negative recall rate for both non-cancer and cancer cases. In clinical practice, physicians will have access to the patient history and scar markers can be used during the image interpretation. Subjects with breast implants and/or breasts too large to be imaged with a single exposure may have been excluded since these subjects would require at least double the number of image acquisitions (implant and implant displaced views and/or mosaic views) on both the clinical system and the investigational device. This amount of imaging may have limited the number of subjects that would be willing to participate in the study and potentially resulting in too few cases for a meaningful analysis of this sub-population. Historically, these exclusions have been used in x-ray based imaging studies to avoid confounding the results of the reader study, not for technical reasons. For example, the x-ray attenuation through scar tissue would be the same regardless of whether the detector was film or FFDM. The performance of a device in the clinical study was considered sufficient to support the use of the device for the general mammography population. In addition, reader experience with interpreting these subjects on film is expected to translate to FFDM. These exclusions were also applied for the clinical studies used to support the initial approval of the Hologic Selenia Dimensions 3D System. There were no additional data requirements or labeling restrictions for these subjects. The original studies were designed to support the use of FFDM plus DBT. There were no technical reasons to exclude the subjects. The standard of care FFDM images would still be available, which would also support the generalizability to these subjects. The panel is asked to consider whether the clinical study results and current labeling are sufficient to support the use of the 3D s exam option with each of these subpopulations. For example, Page 3 of the draft C-View User Instructions specifically notes the potential for breast implants to cause atypical images. Page 4 indicates the C-View software relies on knowledge of breast geometry, which suggests there may also be issues when the breasts are too large to be imaged on a single view. Does the panel recommend that the labeling state that another exam option (FFDM or FFDM plus DBT) should be used for subjects with previous surgical (excisional) biopsy, breast implants, and/or breasts too large to be imaged with a single exposure? The labeling could also indicate that the effectiveness of the device with these patients was not established. Page 28 of 33

29 If the panel believes that the results are not generalizable for one or more groups, then panel is asked to comment on what additional information would be considered necessary to support the use of the device with those subjects. Would an evaluation of the image quality from a set of sample cases be sufficient to support the use with these subpopulations? For example, having a qualified radiologist(s) evaluate whether the image quality is acceptable on a set of representative cases. Panel Discussion: FDA would like panel recommendations regarding the study exclusions. D. Safety No adverse events from the data collection were reported. The benefit and risk discussion compares the differences in radiation dose with FFDM and 3D s. Panel Vote: Is there a reasonable assurance that the device is safe for the proposed indications? E. Effectiveness ROC analysis is an accepted method for reader studies used to evaluate the effectiveness of a new imaging device. The ROC analysis evaluates the performance of a radiologist over a range of decision thresholds (i.e., over a range of sensitivities and specificities); thus, it is useful for measuring the performance of a new imaging modality for which doctors have not yet determined their decision threshold. In clinical practice, the decision thresholds at which a radiologist operates may move along the ROC curve depending upon experience and the desired tradeoff between sensitivity (cancer detection) and specificity (recall rate). The primary non-inferiority endpoint was met. The range of secondary endpoints indicates that the 3D plus synthesized 2D viewers is non-inferior across breast density, calcification/noncalcifications, reader experience, and tomosynthesis experience. In clinical practice, there will likely be differences in the specific performance levels (e.g., AUC, recall rate) since the pivotal study relied on an enriched dataset and the readers were not given the patient history or prior images. However, the results indicate that DBT plus synthesized 2D images are non-inferior to FFDM alone, and this difference may be expected to translate into clinical practice since the study was designed to allow a comparison of the diagnostic ability of the systems with as minimal bias as possible, or if such bias exists, it should not reach the magnitude of the observed difference. Panel Vote: Is there a reasonable assurance that the device is effective for the proposed indications? F. Benefit / Risk The panel is asked to evaluate the benefit/risk with respect to the current standard of care (FFDM). Information on the approved DBT options is provided since the panel may find it useful for reference. Page 29 of 33

30 The potential benefits when using DBT plus synthesized 2D (3D s ) views include: The results suggest 3D s may be more effective for breast cancer screening than FFDM; The results indicate 3D s will reduce the number of non-cancer recalls, which could reduce unnecessary patient anxiety and radiation exposure from additional imaging; Compared with the approved DBT options (FFDM+DBT), the breast compression time is reduced since there is only one acquisition per view; and The radiation exposure is lower than other DBT options. The potential risks when using DBT plus synthesized 2D views include: Compared to FFDM, the radiation dose from the DBT image acquisition is higher, which presents a slight increase in risk of future cancer development from the ionizing radiation. The 3D s acquisition will not include the standard of care FFDM images, which could potentially impact how mammography is performed. Hologic s Executive Summary includes a risk versus benefit analysis based on a number of assumptions from the study, cancer prevalence, and radiation risk. However, the study enrichment makes it difficult to generalize the estimates of recall, sensitivity, specificity and any risk / benefit analysis based on these measures. A comparison of the radiation exposure and results of the prior FFDM plus DBT studies may also help evaluate the benefit and risk. The following tables provides a comparison of the dose for FFDM and DBT views as measured using an ACR breast phantom that simulates a 4.2 cm thick, 5% fat / 5% glandular equivalent compressed breast. There is no additional dose for a synthesized 2D view, since it is reconstructed from the DBT acquisition. With technological advances, the average glandular dose for a single view is now much lower than the MQSA limit 3 for a single view. Table 9. Comparison of radiation dose for a single FFDM and DBT view. Mode Dose for Single View FFDM.2 mgy DBT.45 mgy Synthesized 2D - MQSA Limit 3 3. mgy Table 2 provides a comparison of the radiation dose per breast for the exam (all views). The exam dose for the 3D s option will be greater than FFDM, but less than other approved DBT options. There is no MQSA dose limit for an exam. 3 The Mammography Quality Standards Act (MQSA) states: The average glandular dose delivered during a single craniocaudal view of an FDA-accepted phantom simulating a standard breast shall not exceed 3. milligray (mgy) ( rad) per exposure. [2 CFR 9(e)(5)(vi)] Page 3 of 33

31 Table 2. Comparison of radiation dose for acquisition options. The FFDM+DBT options were approved in the original PMA application. Mode FFDM Views DBT Views Synthesized Exam Dose Views per Breast FFDM MLO + CC mgy FFDM + 3D MLO MLO + CC MLO mgy FFDM + DBT MLO + CC MLO + CC mgy DBT + Synthesized 2D - MLO + CC MLO + CC 2.9 mgy Table 2 compares the increase in ROC AUC with different DBT options. All of the DBT options result in an increase in ROC AUC as compared with FFDM. The dose with 3D s is higher than FFDM, but lower than other DBT options since the FFDM images are not acquired. Table 2. Increase in ROC AUC for DBT acquisition options. The FFDM+DBT values are from the original PMA application. Mode Increase in ROC Increase in Exam AUC over FFDM Dose per Breast FFDM + 3D MLO mgy FFDM + DBT mgy DBT + Synthesized 2D.42 mgy Table 22 presents a simple benefit/risk analysis for, subjects based on the sensitivity and specificity results from the study. The prevalence of cancer is assumed to be %. The cancer recall rate was 83% and 85.4% for FFDM and 3D s respectively; and the non-cancer recall rate was 46.4% and 32.2% for FFDM and 3D s respectively. Note: due to the study enrichment, the sensitivity and specificity will be different from the clinical practice. Table 22. Estimated impact of 3D s based on sensitivity and specificity for, cases. Note: these numbers are from the retrospective cancer-enriched study with limited generalizability to clinical practice. FFDM 3D s Change Cancer True Positives False Negatives Non-Cancer False Positives True Negatives Panel Discussion: FDA would like the panel to discuss the benefit and risks of the new imaging technique. Page 3 of 33