Historical overview of FDA regulation of digital pathology imaging applications: the safety and effectiveness issues

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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• Historical reference standard for surgical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?
Conventional optical microscope
SLIDE
Image Processing software
Digital image sensor
Mechanical scanner
Light source
Imaging optics
Display
READER
IMAGE DATA FILES

• 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

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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