aBSI

{0}------------------------------------------------ August 5, 2019 Image /page/0/Picture/1 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health & Human Services logo on the left and the FDA logo on the right. The FDA logo features the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text. EXINI Diagnostics AB % Donna-Bea Tillman, Ph.D. Senior Consultant Biologics Consulting Group, Inc. 1555 King Street. Suite 300 ALEXANDRIA VA 22314 Re: K191262 Trade/Device Name: aBSI Regulation Number: 21 CFR 892.2050 Regulation Name: Picture archiving and communications system Regulatory Class: Class II Product Code: LLZ Dated: May 9, 2019 Received: May 10, 2019 Dear Dr. Tillman: We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading. If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR 803) for {1}------------------------------------------------ devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems. For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100). Sincerely. For Thalia T. Mills, Ph.D. Director Division of Radiological Health OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health Enclosure {2}------------------------------------------------ ## Indications for Use 510(k) Number (if known) k191262 Device Name aBSI Indications for Use (Describe) aBSI is intended to be used by trained healthcare professionals and researchers for acceptance, transfer, storage, image display, manipulation, quantification and reporting of digital medical images acquired using nuclear medicine (NM) imaging. The device provides general Picture Archiving and Communications System (PACS) tools as well as a clinical application for oncology including lesion marking and quantitative analysis. Type of Use (Select one or both, as applicable) | <span> <span style="font-size: 16px;">☑</span> Prescription Use (Part 21 CFR 801 Subpart D) </span> | |-------------------------------------------------------------------------------------------------------| | <span> <span style="font-size: 16px;">☐</span> Over-The-Counter Use (21 CFR 801 Subpart C) </span> | ### CONTINUE ON A SEPARATE PAGE IF NEEDED. This section applies only to requirements of the Paperwork Reduction Act of 1995. ### *DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.* The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to: > Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov "An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number." {3}------------------------------------------------ In accordance with 21 CFR 807.87(h) and (21 CFR 807.92) the 510(k) Summary for the aBSV is provided below. #### SUBMITTER 1. Applicant: EXINI Diagnostics AB Ideon Science Park Scheelevägen 27 223 70 Lund Sweden Aseem Anand, Ph.D. Contact: Vice President EXINI Diagnostics AB Ideon Science Park, Scheelevägen 27, SE-223 70 Lund, Sweden Tel: +46706604084 aseem.anand@exini.com Donna-Bea Tillman, Ph.D. Submission Correspondent: Senior Consultant Biologics Consulting 1555 King Street, Suite 300 (410) 531-6542 dtillman(@biologicsconsulting.com #### 2. DEVICE Date Prepared: | Device Trade Name: | aBSI | |---------------------|-----------------------------------------------------------| | Device Common Name: | Picture Archiving and Communications System<br>(PACS) | | Classification Name | 21 CFR 892.2050 System, Image Processing,<br>Radiological | | Regulatory Class: | II | | Product Code: | LLZ | May 9, 2019 ### 3. PREDICATE DEVICE Predicate Device: EXINI (K122205) K191262 {4}------------------------------------------------ #### DEVICE DESCRIPTION 4. The aBSI is a software-only medical device that provides a fully quantitative assessment of a patient's skeletal disease on a bone scan, as the fraction of the total skeleton weight. The user of this product is typically a health-care professional using the software to view the patient images and analysis results. ### INTENDED USE/INDICATIONS FOR USE ನ. aBSI is intended to be used by trained healthcare professionals and researchers for acceptance, transfer, storage, image display, manipulation, quantification and reporting of digital medical images acquired using nuclear medicine (NM) imaging. The device provides general Picture Archiving and Communications System (PACS) tools as well as a clinical application for oncology including lesion marking and quantitative analysis. ### SUBSTANTIVE EQUIVALENCE 6. ## Comparison of Indications The image modality computed tomography (CT) has been removed from the intended use for aBSI compared to EXINI. The ability to also display CT images was a feature introduced in EXINI to allow for simultaneous viewing of both types of images. CT images are not required or used for BSI calculation and this feature was rarely used. Therefore, this feature has been removed and CT images are not accepted by the aBSI device. This change does not affect the fundamental intended use of the device, and EXINI can be used as a predicate for aBSI. ## Technological Comparisons The table below compares the key technological features of the subject devices to the predicate device | | <i>EXINI</i> (predicate device) | <i>aBSI</i> (subject device) | Discussion of Differences | |---------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | Intended user | Health care professionals and<br>researchers | Same | - | | Intended use<br>environment | Health care clinics | Same | - | | Classification | System, Image Processing,<br>Radiological (LLZ)<br>21 CFR 892.2050 | Same | - | | Installation | Product CDs or downloadable<br>installation files | Cloud-based service and<br>access with personal log-in. | Does not affect the clinical<br>use of the device | | Operating system | Microsoft Windows | Microsoft Windows or<br>macOS with Chrome browser | Does not affect the clinical<br>use of the device | | | <i>EXINI</i> (predicate device) | <i>aBSI</i> (subject device) | Discussion of Differences | | DICOM<br>compatibility | DICOM 3:<br>• Whole body bone scans<br>• Static (partial) bone scans<br>• SPECT/CT | DICOM 3:<br>• Whole body bone scans<br>• SPECT | Static (partial) bone scans<br>and CT images are not<br>required or used for BSI<br>calculation. | | Image upload | Via DICOM SCP or folder on<br>local computer or network | Via folder on local computer<br>or network | Does not affect the clinical<br>use of the device | | Support for<br>multiple Bone<br>Scans | Yes, if multiple scans are<br>provided, the images are<br>automatically aligned vertically | Same | - | | Colormaps | A selection of commonly used<br>colormaps | Sub-Selection of previously<br>provided colormaps. | Optimal colormaps<br>continue to be provided | | Zoom | Manually adjustable image size<br>Zoom | Automatically adjusted image<br>size<br>Zoom | To improve the efficiency<br>of <i>aBSI</i> automatic<br>adjustment of images to<br>screen size | | Windowing | • Automatic adjustment of<br>maximum and minimum<br>thresholds for image windowing<br>• Manual adjustment of<br>maximum and minimum<br>thresholds | • Automatic adjustment of<br>maximum and minimum<br>thresholds for image<br>windowing (same)<br>• Manual adjustment of<br>maximum and minimum<br>thresholds has a wider range | Both devices show<br>normalized images at<br>startup and have<br>adjustable min and max<br>thresholds for image<br>windowing. | | Intensity display | Local intensity displayed at<br>mouse pointer when hovering<br>over image | Local intensity displayed in<br>left corner of the image when<br>hovering over image | To improve visibility of<br>the intensity | | Image layouts | • Anterior and posterior images<br>shown side by side<br>• Mirror tool for switching<br>between the anterior and<br>posterior image in the same<br>image frame | • Anterior and posterior<br>images shown side by side | Removal of feature does<br>not impact clinical utility<br>of the device | | Image Quality<br>Control | • Total image intensity<br>displayed<br>• Skeletal image count<br>displayed | • Total image intensity<br>displayed | Both devices display total<br>image intensities. Total<br>image intensity is the<br>common way of assessing<br>image quality, therefore<br>total skeletal intensity is<br>not needed. | | Hotspot display | • Hotspots displayed in image<br>• Hotspot involvements are<br>displayed in tables. One table<br>per scan. | • Hotspots displayed in image | Both devices display<br>hotspots in the images. | | | <i>EXINI</i> (predicate device) | <i>aBSI</i> (subject device) | Discussion of Differences | | Segmentation of<br>skeletal atlas | Segmentation of skeletal atlas<br>covering the area from the skull<br>down to ¾ of the femur and<br>humerus. | Segmentation refined, and<br>skeletal area covered by the<br>atlas increased to cover the<br>entire femur and humerus. | Allows for detection of<br>hotspots further out in the<br>limbs. | | Normalization | Images are normalized so that<br>healthy bone tissue intensities<br>are automatically set to a<br>predefined level. | Same | - | | Hotspot detection | Algorithm to detect high<br>intensity regions of interest<br>within the skeletal atlas. | Improved algorithm to detect<br>of high intensity regions of<br>interest within the skeletal<br>atlas. | Results of clinical<br>performance testing<br>demonstrate substantially<br>equivalent performance. | | Summary page<br>export | Supported | Supported | - | | CSV export | N/A | Supported | This feature was<br>implemented to facilitate<br><i>aBSI</i> use in research<br>studies. | Technological Comparison Table 1: {5}------------------------------------------------ {6}------------------------------------------------ The EXINI was cleared in 2012 with BSI quantification as an integral feature. Since its clearance, the device algorithm has evolved, and the device is now hosted in cloud infrastructure. However, the essential BSI quantification feature of the device remained substantially equivalent. ### PERFORMANCE DATA 7. # Biocompatibility Testing There are no direct or indirect patient-contacting components of the subject device. Therefore, patient contact information is not needed for this device. # Electrical safety and electromagnetic compatibility (EMC) Not applicable. The subject device is a software-only device. It contains no electric components, generates no electrical emissions, and uses no electrical energy of any type. # Software Verification and Validation Testing Software verification and validation testing were conducted and documentation was provided as recommended by FDA's Guidance for Industry and FDA Staff, "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices." The software for this device was considered as a moderate level of concern because, although unlikely, an incorrect BSI value could potentially contribute to the risk of an incorrect therapy decision or delay in the delivery of appropriate care. {7}------------------------------------------------ # Bench Testing EXINI Diagnostics conducted verification to demonstrate the performance of the device, including: - . A set of analytical validation studies to evaluate the performance of the aBSI v3.4 in quantifying bone scans, including: - Linearity & Accuracy of BSI calculation o - Precision of BSI calculation O - Reproducibility with different cameras O - o Reproducibility with multiple images - Patient study to demonstrate Reproducibility of BSI calculation with Repeated Bone Scans - Comparison testing using a phantom simulation to compare the bone scan index determined with predicate EXINI 1.7 to that the subject device aBSI. # Animal Testing Not applicable. Animal studies are not necessary to establish the substantial equivalence of this device. # Clinical Data Results from the two clinical studies comparing aBSI assessment to standard interpretation of bone scan demonstrated the utility of aBSI device against the state of the art (PCWG criteria) and essential clinical outcomes. | Study<br>Number | Title | Objective | Design | Patients | |-----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|-------------------------------| | I | Phase 3 validation of the<br>automated Bone Scan Index<br>association with overall<br>survival in men with metastatic<br>castration-resistant prostate<br>cancer | Association of <i>aBSI</i> with<br>clinical outcome –<br>overall survival,<br>progression free survival,<br>opioid induced survival | Prospective Planned<br>Analysis – A multi-site<br>study phase III: NTC<br><b>01234311</b> | Prostate<br>Cancer<br>(N=721) | | II | Optimizing Radiographic<br>Progression Free Survival by<br>Prostate Cancer Working<br>Group (PCWG) Criteria using<br>the Automated Bone Scan<br>Index ( <i>aBSI</i> ) | Comparison of <i>aBSI</i><br>increase against counting<br>number of new lesions<br>(by PCWG criteria) in<br>radiographic progression | Retrospective study at<br>Memorial Sloan Kettering<br>Cancer Center – single site | Prostate<br>Cancer<br>(N=169) | Study I involved a prospectively defined analysis of patients in a phase 3 international, multicenter study. This phase 3 study was a multicenter randomized, double-blind, placebocontrolled study of tasquinimod (10TASQ10) in metastation-resistant prostate cancer mCRPC patients. Study subjects were recruited at 241 sites in 37 countries (including the US). {8}------------------------------------------------ Of the total 1245 phase 3 patients enrolled in 37 countries, 721 patients were evaluable with aBSI. The aBSI population was representative of the total study population based on baseline characteristics. Automated BSI (median=1.07; range: 0-32.60) was significantly associated with OS (HR:1.20; 95%CI:1.14-1.26; P<0.001). Median OS by automated aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. In a multivariate survival model, the automated aBSI remained independently associated with OS (HR:1.06; 95%CI:1.01-1.11; P=0.03). The automated BSI was also independently associated with symptomatic progression (HR:1.18: 95%Cl:1.13-1.23: P<0.001). and time to opiate use for pain (HR:1.21: 95%Cl:1.15-1.29; P<0.001). The results of Study I provide compelling evidence that the clinical performance of quantitative aBSI assessment is additive to the existing clinical parameters. In Study II, patients at Memorial Sloan Kettering Cancer Center (MSKCC) with metastatic prostate cancer (mCRPC) were enrolled in Phase II/II clinical trials of agents targeting the androgen receptor (AR) signaling axis and were assessed retrospectively for this analysis. A total of 257 patients were assessed, of whom 169 had bone scans available for the aBSI analysis. The median aBSI at baseline was 3.1 (IOR: 1.3 - 7.1). An increase in aBSI was associated with OS at a Kendall's Tau of 0.52 when the aBSI increased by 0.6. An aBSI increase beyond 0.6 from first follow-up did not result in further improvement in the association with OS. The same association of time to radiographic bone progression was observed (0.52) with PCWG criteria. Of the 169 patients, 90 (53%) had progression in bone cancer that met the PCWG criteria. The total aBSI increase in patients that met the PCWG criteria was 1.22 [IQR: 0.65-2.49] and a median relative increase of 109% [IQR: 40-377%]. These results demonstrate that the total quantitative assessment of increase in skeletal disease burden, with aBSI assessment, has the same association with overall survival as that defined by PCWG criteria. ### CONCLUSION 8. Based on the detailed comparison between the predicate devices and the subject devices, the performance testing and clinical data, the aBSI can be found substantially equivalent to the predicate device.