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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

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Outline

• Define digital pathology

• Intended Use

• Reference standard-Light microscope

• IVDs that utilize digital imaging

• Lessons from Radiology

• Safety and effectiveness issues

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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

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Intended Use

• Primary diagnosis of surgical pathology microscope slides in lieu of a microscope

• Not an adjunct

• Broad application (not organ or disease specific)

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21 CFR 864.3600Microscopes 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• Historical reference standard for surgical pathology diagnosis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.

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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

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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

Mechanicalscanner

Lightsource

SLIDE

Imagingoptics

Digitalimagesensor

ImageProcessing

software Display

READERIMAGEDATA FILES

Conventionaloptical microscope

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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

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IVD devices that utilize digital imaging

• Immunohistochemistry image analysis applications– i.e. HER2, ER– Used as an adjunct to

quantitate amount of “brown” stain

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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

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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

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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

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Conclusion

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

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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

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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

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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

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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)

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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)

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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

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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