1. 1 Historical overview of FDA regulation of digital pathology imaging applications: the safety and effectiveness issues Tremel A. Faison, MS, RAC, SCT(ASCP) FDA/CDRH/OIVD/DIHD

2. 2 Outline Define digital pathology Intended Use Reference standard-Light microscope IVDs that utilize digital imaging Lessons from Radiology Safety and effectiveness issues

3. 3 Digital Pathology The use of computer technology to convert analog microscopic images into digital images Whole slide imaging (WSI), aka digital imaging, virtual slides, virtual microscopy System consisting of hardware; microscope, camera, scanner, computer, and monitor, and software. Encompasses image acquisition, processing, archiving and retrieval

4. 4 Intended Use Primary diagnosis of surgical pathology microscope slides in lieu of a microscope Not an adjunct Broad application (not organ or disease specific)

5. 5 21 CFR 864.3600 Microscopes and accessories Historical reference standard for surgical pathology diagnosis Optical instruments used to enlarge images of specimens, preparations, and cultures for medical purposes Class I (general controls) exempt from premarket notification (510k) subject to limitations in 864.9.

6. 6 21 CFR 864.9 Limitations of exemptions from 510(k) (a few) Exemption only to the extent that misdiagnosis as a result of using the device would not be associated with high morbidity or mortality –Different fundamental scientific technology –IVD intended for use in diagnosis, monitoring or screening of neoplastic diseases

7. 7 What does this mean? Microscope one component of the system Image acquisition, processing and display new technology for this intended use Diagnostic for neoplastic disease WSI systems can not be considered Class I exempt Mechanical scanner Light source SLIDE Imaging optics Digital image sensor Image Processing software Display READER IMAGE DATA FILES Conventional optical microscope

8. 8 IVD devices that utilize digital imaging 21 CFR 864.5260 Automated cell-locating devices Examples Automated hematology analyzers (differential cell counters) Chromosome analyzers FISH enumeration systems Urine sediment analyzers

9. 9 IVD devices that utilize digital imaging Immunohistochemistry image analysis applications –i.e. HER2, ER –Used as an adjunct to quantitate amount of “brown” stain

10. 10 IVD devices that utilize digital imaging Manual Read of Digital Image –Immunohistochemistry with no image analysis –Pathologist performs estimation of stain intensity and percent positivity from digital image alone –Limited to Breast PR and HER2 applications

11. 11 IVD devices that utilize digital imaging Gynecologic Cytology Imaging Systems –Cytyc/Hologic ThinPrep Imaging System –Becton Dickinson/TriPath FocalPoint Guided Screening System –Papanicolaou Stain –Class III devices –Detection algorithm, neural network

12. 12 None of these examples can be directly applied to digital whole slide imaging Each of these devices has a specific and limited intended use that is not applicable to WSI for the breadth of surgical pathology specimens

13. 13 Conclusion WSI raises new questions of safety and effectiveness that must answered through premarket submission requirements

14. 14 What are our concerns? Is the WSI presented of such quality that the same diagnosis could be made as when using the light microscope for all surgical pathology specimens? What are differences in use between the two methods? i.e. viewing and navigating on a computer screen vs. a light microscope Serious consequences to public health if misdiagnosis is caused by poor quality image or improper use

15. 15 What can we learn from radiology? Similarities between switch from film to digital mammography 21 CFR 892.2010 Medical image storage device 21 CFR 892.2020 Medical image communications device 21 CFR 892.2030 Medical image digitizer 21 CFR 892.2040 Medical image hardcopy device 21 CFR 892.2050 Picture archiving and communications system

16. 16 Determination of safety and effectiveness 21 CFR 860.7 Intended use population Conditions of use for the device Probable benefit to health from the use of the device weighed against any probable injury of illness Reliability of the device

17. 17 Safety Reasonable assurance, based on valid scientific evidence, that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use, outweigh any probable risks 21 CFR 860.7(d)(1)

18. 18 Effectiveness Reasonable assurance, based on valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended use and conditions of use, when accompanied by adequate directions for use and warning against unsafe use, will provide clinically significant results 21 CFR 860.7(e)(1)

19. 19 How does FDA plan to ensure the safety and effectiveness of digital pathology devices? Require analytical and clinical studies to objectively and precisely validate performance Knowledge of the risks, benefits and limitations Standardization Postmarket studies

20. 20 Summary FDA recognizes that the technological advances associated with WSI make its use a reality WSI systems are not Class I exempt and are therefore, subject to premarket requirements Current IVDs that utilize digital imaging for limited applications are not applicable to the WSI paradigm Digital mammography may provide useful lessons but does not address all of the concerns for WSI Our goal is to gain information about the technology in order to ensure safe and effective use