1. Tremel A. Faison, MS, RAC, SCT(ASCP) FDA/CDRH/OIVD/DIHD
Historical overview of FDA regulation of digital pathology imaging applications: the safety and effectiveness issues
My name is Tremel Faison and I’m a scientific reviewer in the Office of In Vitro Diagnostic Device Evaluation and Safety, Division of Immunology and Hematology Devices. I’d like to welcome you to this panel meeting regarding Digital Pathology. I, as I’m sure you are, am looking forward to a productive and informative two days. Advances in technology, such as improved image software, scanning throughput, and image storage capabilities have made the wide spread use of digital imaging systems for primary diagnosis a reality. if not now. in the near future. Today I’d like to give you historical overview of FDA regulation of digital imaging devices in OIVD, the use of digital imaging is not new in the clinical or anatomic laboratory---OIVD has cleared and approved several digital imaging devices with limited adjunctive applications. We believe the use of digital imaging for surgical pathology raises new safety and effectiveness issues that must be addressed. We recognize the many benefits the technology provides, at the same time we need to be sure of it’s limitations to prevent risk to public health.
Tremel A. Faison, MS, RAC, SCT(ASCP)
FDA/CDRH/OIVD/DIHD

2. Outline Define digital pathology Intended Use
Reference standard-Light microscope
IVDs that utilize digital imaging
Lessons from Radiology
Safety and effectiveness issues
First I’ll define digital pathology and the intended use for the scope of this meeting. Next, I’ll talk about the historical reference standard-the light microscope. We’ll discuss some examples of IVDs that utilize digital imaging and their intended uses. The switch from film to digital radiology while not totally applicable can provide some valuable lessons to draw from. Lastly, we’ll discuss our concerns about DP devices and the associated safety and effectiveness issues.

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
Digital pathology is the use of computer technology to convert analog microscopic images into digital images. For this meeting we will be using the term whole slide imaging, abbreviated “WSI”, also known as digital imaging, virtual slides, or virtual microscopy. I’m sure there are other synonyms out there. Whole slide imaging systems consist of hardware—a microscope, camera, scanner, computer and monitor and the accompanying image software. The system performs image acquisition, processing, archiving and retrieval.

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)
Everything here at the FDA starts with the intended use. Intended use shapes how the device will be regulated, in what population and ultimately-the study design. For the scope of this panel meeting the intended use is defined as the use of WSI for primary diagnosis of surgical pathology microscope slides in lieu of a microscope. This is not an adjunctive intended use and for our purposes we will be considering the use of WSI for all surgical pathology specimens---it is not organ or disease specific.

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
The historical reference standard for the intended use described is the light microscope. They are defined as medical devices under the Code of Federal Regulations 21 CFR as optical instruments used to enlarge images of specimens, preparations, and cultures for medical purposes. Microscopes are class I exempt from premarket notification subject to limitations in

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
Here are a few of the limitations of exemptions from 510(k) that are applicable to WSI. Exemption is only to the extent that misdiagnosis as a result of using the device would not be associated with high morbidity or mortality---If there is a different fundamental scientific technology or the device is an IVD intended for use in diagnosis, monitoring or screening of neoplastic the device does not qualify for exemption.

7. What does this mean? Microscope one component of the system
Conventional
optical microscope
SLIDE
Image
Processing
software
Digital
image
sensor
Mechanical
scanner
Light
source
Imaging
optics
Display
IMAGE
DATA FILES
READER
So, what does all of that “regulatory language” mean? Here is a graphic of each of the components in WSI systems. As you can see the optical microscope is only one component of the system. We consider other components such as, image acquisition, processing and the display new technology for this intended use. In addition the use of WSI for primary diagnosis of surgical pathology specimens encompasses not only neoplastic disease but the entire spectrum of human pathologic diagnoses and carries the risk of serious public health consequences if erroneous results are rendered using these systems. Therefore, WSI can not be considered exempt from premarket submission requirements.
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

8. IVD devices that utilize digital imaging
21 CFR Automated cell-locating devices
Examples
Automated hematology analyzers (differential cell counters)
Chromosome analyzers
FISH enumeration systems
Urine sediment analyzers
If WSI imaging devices aren’t class 1 then are there any other digital imaging devices in IVD that we’ve had past experience with?
Automated cell-locating devices are regulated as Class II and encompass a variety of different types of device, some examples include automated hematology analyzers used to provide differential cell counts in blood or body fluids, chromosome analyzers pictured here in the upper right, and fish enumerations systems in the lower right, and urine sediment analyzers. What they all have in common is that these devices locate, count and identify cells, and must have final interpretation by a trained user.

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
Image analysis devices have been used as an adjunct to light microscopy diagnoses to quantify the amount of brown stain for immunohistochemistry stains such as HER2/neu and estrogen receptors. These devices are only used after the primary diagnosis is made under the light microscope.

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. 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
Lastly, gynecologic cytology imaging systems use detection algorithms and/or neural networks to detect abnormal cells on Pap smears. These are class III devices that aid in the identification of the abnormal cells for the cytotechnologist and perform no diagnosis. In fact diagnosis is still made on the abnormal cases under the light microscope.

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

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

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. What can we learn from radiology?
Similarities between switch from film to digital mammography
21 CFR Medical image storage device
21 CFR Medical image communications device
21 CFR Medical image digitizer
21 CFR Medical image hardcopy device
21 CFR Picture archiving and communications system
So what can we learn from radiology. There are many similarities between the switch from film to digital mammography that pertain to digital imaging and there are several radiology regulations that can serve as examples. I won’t go in to detail here ---tomorrow Dr. Myers will discuss the safety and effectiveness issues and regulatory requirements for digital mammography. Regretably many of the tough issues associated with WSI are different and have more subtleties than digital radiology. However digital radiology does give us a nexus to begin discussion on how to determine the safety and effectiveness of WSI.

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
How to determine safety and effectiveness is detailed in 21 CFR where it states that we must consider the intended use population that the device will be used on, the conditions of use for the device, the probable benefit to health from the use of the device weighed against any probably injury of illness and reliability of the device.

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)
Furthermore,

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. 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
….and if enough information isn’t available from the premarket studies we may require postmarket studies. We are seeking input from the panel on these issues.

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
…..Just a note for the panel members the set of questions in the panel packet have been condensed from the original version that was sent to you earlier.