FAQs

Digital pathology broadly refers to a discipline in which digital tools are used to advance the practice of pathology, to educate trainees, or to promote discovery.  These tools include digital imaging technologies (e.g. whole-slide imaging), telepathology, and data science methods such as data mining, digital image analysis, and artificial intelligence.

• Consultation from off-site pathologists with a shorter turnaround time
• Telepathology for frozen section to benefit patients undergoing operative procedures
• International collaboration, consults, and helping underserved areas
• Improved organization, reduced possibility of missing slides
• Digital images as part of a patient’s medical record
• Measurement and counting, including quantitative and automated analysis
• Workflow automation
• Efficient slide archival

It is recommended by the College of American Pathologists (CAP), a CLIA accredited organization, that all institutions or practices considering the implementation of digital pathology for clinical diagnostic purposes must carry out their own validation.  For more information please refer to the Regulatory page.

It is recommended by the College of American Pathologists (CAP), a CLIA accredited organization, that all institutions or practices considering the implementation of digital pathology for clinical diagnostic purposes must carry out their own validation. However, it is up to the institution or practice who has implemented the digital pathology system to determine the scope of the validation study; specifically what will and will not be included as an intended use. Refer to the institution performing the technical component (TC) for information on their validation of the digital pathology system and whether or not it is validated for the professional component (PC) of a primary or secondary diagnosis.

To view the current cleared/approved FDA devices, please refer to the FDA database. Potential codes to search for include QKQ, PZZ, OEO, NQN or NOT. For CPT codes, please refer to the CMS website and search in the Pathology directory. The most commonly used code for image analysis is 88361. Some manufacturers have obtained 510(k) clearances for manual and/or quantitative analysis of Immunohistochemistry and/or FISH. Please refer to the 510(k) clearance list and the Regulatory page for more information.

Whole-slide imaging is the high-resolution digital capture of glass slides to generate “virtual slides.” It consists of a microscope designed to scan one or more slides in an automated fashion (the whole-slide scanner) and accompanying image viewing software that allows users to navigate a slide in a manner similar to Google Maps. It may optionally include an image management platform that provides controlled access and organization, educational tools, and image analysis software for computer-assisted measurement.

Virtual slides are usually stored in a proprietary format which can be viewed by the image viewing software provided by the vendor. However, some viewers are vendor-neutral and can support multiple image formats. Some of these are freely available.

There has been a great deal of debate about the differences in the experience of viewing a slide digitally or under a microscope. However, a recent multi-institutional validation study reported whole slide imaging to be non-inferior to glass slide microscopy [link]. The College of American Pathologists has provided validation guidelines for institutes planning to use whole-slide imaging [link].

Yes, Whole Slide Imaging device for primary diagnostic use can be legally marketed in the US, please click here and here. Please refer to the regulatory page for more information.  

Some whole-slide scanners support fluorescence imaging in addition to brightfield viewing.

Many whole-slide scanners can optionally capture multiple focal planes of the same glass slide arranged in a z-stack. Often, users can select the number of focal planes to capture and the plane spacing (or total range). Z-stacks can usually be incorporated into a single file. However, two main challenges presently exist: 1) the file sizes produced can be quite large and 2) the image viewer must support z-stacking. Computational methods have been developed to collapse z-stacks into a single plane representing the “in focus” region, which may mitigate these challenges but would no longer allow the user to traverse the z-stack in its entirety.

Most scanners support resolutions of 0.5 microns/pixel (effective viewing magnification: 20X) or 0.25 microns per pixel (effective viewing magnification: 40X). Following image compression, the image files produced may exceed 1 GB in size each. Some whole-slide scanning vendors allow the user to modify the compression quality factor, enabling users to manage the tradeoff between image quality and file size. Users have the option of storing images in the cloud, on local servers, or on local workstations.

Virtual slides are rarely stored in their raw form. Usually, they are compressed (lossy or losslessly) by the whole-slide scanner during capture. Lossless compression refers to an image compression method in which no information is lost. This method may reduce raw file sizes by a factor of 4 or more. Lossy compression typically achieves lower file sizes (a reduction by a factor of 20-30 is common) but may reduce image quality. Users should decide the amount of image compression they can tolerate to optimally balance the tradeoff between file size and image quality.

Yes, cloud technology or Storage as a Service (SaaS) is growing in popularity and offers some significant benefits for primary storage and for replication of data.  Cloud based storage can lower storage costs, maintain or improve security and data integrity including HIPPA compliance, improve flexibility, and expand capacity when capacity resources are strained.  More information on cloud replication of data is provided in the DPA white paper “Archival and Retrieval in Digital Pathology Systems.”

HIPAA compliance should be checked and assured with providers of digital pathology solutions. Most vendors have arrangements for encryption of patient identifying data like dates, medical or pathology numbers, labels, and restricting access. Some platforms also support de-identification procedures.

DICOM (Digital Imaging and Communications in Medicine) is the international standard to transmit, store, retrieve, print, process, and display medical imaging information. DICOM makes medical imaging data interoperable by enabling integration of image acquisition devices, archive solutions and workstations across different vendors. In radiology, the DICOM standard is universally used. DICOM has been deployed in hundreds of thousands of medical imaging devices worldwide, with hundreds of billions of DICOM images archived to date.

Yes. DICOM’s Working Group 26 (WG-26) was established in 2005 to develop and extend the DICOM medical imaging standard for pathology and whole slide imaging (WSI). Since then, WG-26 has made two major contributions to the DICOM standard by finalizing the specimen & pathology supplement (2008) and the whole slide imaging supplement (2010). Together, these supplements allow whole slide images containing multi-resolution, pyramidal, z-stacked and multi-spectral pixel data, as well as the related clinical, patient and specimen preparation steps (e.g. fixation, embedding, staining, etc.) to be handled in a standard, open and interoperable fashion.

Scan time is determined by how much tissue is on the slide, the magnification to be acquired (20X or 40X), and how many focal planes are to be acquired (z-stack size). In general, most modern scanners can acquire a 15mm x 15mm region at 40X in about 4-8 minutes. This does not take into account the time it takes to transfer the file from the scanner to its ultimate destination (e.g. a network server).

Four integration options commonly exist: 1) Direct delivery of selected image regions (snapshots) to the patient record in the LIS or EHR; 2) Cataloging of the whole-slide image in the LIS or EHR, so that users can navigate to an image management or PACS system from within the patient record to view the whole-slide image in its entirety; 3) The electronic delivery of whole-slide image-derived data, such as IHC scoring; 4) Document delivery in which an imaging report is issued and attached to the patient record.

Unlike chemistry and other analyzers, the scanner is not considered a high complexity instrument by CLIA and CAP. But the instrument does take skill to maintain and operate.  Someone in the lab— usually a histotechnologist— can assume the role of “scanning tech” and be appropriately trained.  Vendors usually have a training course, but techs can also attend the DPA-NSH whole-slide imaging course.  The course, consisting of 22 hours of training, is not mandatory but shows a level of professionalism appropriate for this important function.  At the completion of the course, the tech (or pathologist) will receive a certificate.  There is a discount for DPA and NSH members.

All digital pathology systems have a calibration process to ensure the scanner produces consistent, high quality whole slide images. However the calibration technique and process will be different for each manufacturer. Therefore, discuss the calibration process with your digital pathology provider.

If your image analysis software is compatible with proprietary whole slide image formats then no calibration is needed. However, if you are working with an unsupported format or with a static “snapshot” from a whole slide image, then yes you will have to manually calibrate the image for accurate image analysis results.

Digital Pathology can be used to streamline the drug development process through discovery, preclinical, and clinical trials by enabling pathologists to more efficiently illustrate, communicate, and collaborate on crucial findings in tissue based toxicity and efficacy studies. A few benefits of digital pathology include high throughput scanning of glass slides, quantitative analysis of whole slide images, immediate web based consultations with expert pathologists, and secure archival of pathology data. Coupled with computer-based interpretation algorithms, digital image analysis (DIA), digital pathology can assess more complex features in the slide images, having the potential to identify patient groups that have increased drug efficacy, increasing the efficiency and likelihood of success of drugs in clinical trials. In addition, DIA could support regulatory CDx submissions as it reduces variability, increasing success rate of reproducibility and multi-site precision studies.

No, but you can create a validation plan to establish a GLP and CFR compliant environment to work with your digital pathology system.  Please refer to the life science Regulatory page for additional information or the DPA white paper “Validation of a Digital Pathology System in the Regulated Non-clinical Environment.”

Yes, please refer to the life science Regulatory page for additional information or the DPA white paper “Validation of a Digital Pathology System in the Regulated Non-clinical Environment.”

Costs can vary considerably depending on the features needed and slide capacity of the scanner. Typically, a whole-slide scanner costs between $50,000 and $300,000, ranging from a single slide capacity to several hundred slides. Scanners come packaged with an image viewer, but many include more sophisticated viewing tools, image management platforms, or image analysis software. Some users opt to purchase software solutions separately, which can add to the total cost of the scanner but can provide additional function or a more seamless integration into existing information systems. Additional cost considerations include IT infrastructure (e.g. storage, data management) and personnel to manage and operate the device.

The Food, Drug, and Cosmetic (FD&C) Act’s definition of medical device (Section 201(h) encompasses IVD products. FDA regulations e(21 CFR 809.3(a)) define in vitro diagnostics specifically as “those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. These products…may also be biological products subject to section 351 of the Public Health Service Act, including when the manufacturer of these products is a laboratory.”

FDA’s LDT Final Rule amended the IVD definition in 21 CFR 809.3(a) to include IVDs manufactured by a laboratory. As revised, the definition now states: “In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. These products…may also be biological products subject to section 351 of the Public Health Service Act, including when the manufacturer of these products is a laboratory.” (emphasis added).

The preamble to FDA’s Final Rule does not directly address digital pathology tools. Therefore, extrapolation of how the LDT Final Rule will apply to digital pathology requires some conjecture based on the current regulatory approach for digital pathology tools.

Digital pathology tools used to support generation of patient results (e.g., primary diagnosis) are IVD medical devices. If your laboratory uses digital pathology tools to report patient results, and the end-to-end system is FDA cleared for this use, then you are using the IVD medical device on label and this is likely not considered an LDT subject to the LDT Final Rule.

However, if your laboratory uses digital pathology tools to support generation of patient results and the components of the test system used to generate, view, and/or analyze whole slide images (WSIs), such as the scanning instrument, viewing software, digital display, and/or analysis application, have not been FDA-cleared together as an end-to-end system, your digital pathology system may be considered an LDT. In this case, the system you are using could be subject to FDA’s Final Rule, which would require compliance with the relevant provisions of the Rule to continue to use this system after the phaseout period ends.

In general, enforcement discretion means that FDA has the authority to regulate a product, but FDA has chosen not to enforce the applicable legal requirements. Prior to the Final Rule, FDA took the position that all LDTs (and laboratories manufacturing them) were subject to the FD&C, but FDA generally chose not to take enforcement action as violations of the Act when a laboratory offered an LDT under CLIA regulations. 

In the Final Rule, FDA explains: 

Although FDA is phasing out its current general enforcement discretion approach over a period of years, the phaseout policy does not in any way alter the fact that it is illegal to offer IVDs without complying with applicable requirements. Regardless of the phaseout timeline and enforcement discretion policies for certain IVDs discussed below, FDA retains discretion to pursue enforcement action for violations of the FD&C Act at any time.[1]

In summary, under its previous policy, FDA was not enforcing any FD&C requirements with respect to  most LDTs offered by clinical laboratories. Under the LDT Final Rule FDA has narrowed the categories of LDTs for which it will extend enforcement discretion, and also has established tiers of enforcement discretion, with some tests subject to all IVD requirements, some subject to only a subset of those requirements, and others that remain under complete enforcement discretion.

[1] 89 Fed. Reg. 37295.

The following categories of LDTs will continue to be subject to complete enforcement discretion (i.e., not subject to any of the phaseout Stages for the Final Rule):

 1.     LDTs for Human leucocyte antigen (HLA) testing for transplantation:

• to perform HLA allele typing;
• for HLA antibody screening and monitoring; or
• for conducting real and virtual HLA crossmatch tests

2.     1976-Type LDTs

• Tests that have the following characteristics common among LDTs that were offered in 1976:
  • Involve the use of manual techniques (i.e., without automation[1])
  • Are performed by laboratory personnel with specialized expertise;
  • Use components legally marketed for clinical use; and
  • Are designed, manufactured, and used without a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing.
• Examples of tests that might be considered 1976-Type LDTs when done manually and without automation (e.g., without use of software) include:
  • various tests that use staining antibodies and general purpose reagents for cytology, hematology, and bacterial infections;
  • cystic fibrosis sweat tests;
  • certain colorimetric newborn screening tests;
  • certain immunohistochemistry tests; karyotyping tests; and fluorescence in situ hybridization (FISH) tests;
  • adsorption of warm-reactive autoantibodies using allogeneic or autologous red blood cells to prepare samples for further immunohematology testing;
  • This category would not generally include, e.g., lateral flow tests, as they do not generally rely on laboratory personnel expertise.
• FDA intends to consider whether guidance containing additional discussion and examples of tests that may fall within this category would be helpful.

3.     LDTs manufactured and performed within the Veterans Health Administration (VHA) or the Department of Defense (DoD)

These three categories  of LDTs can continued to be offered under the enforcement discretion approach that preceded  the LDT Final Rule.

 Certain categories of LDTs will be subject to partial enforcement discretion.  As described in the Table below, these categories will remain under enforcement discretion with respect to premarket authorization requirements but will be subject to at least some of the requirements described in Stages 1, 2, and 3 of the Final Rule phaseout period.

*See Q7/A7 for a description of the requirements and timing for compliance

FDA will phase out enforcement discretion, and phase in medical device requirements, over a period of four years. The Phaseout Policy is divided into 5 Stages, as described in the Table below.

The preamble to FDA’s Final Rule does not directly address digital pathology tools. Therefore, extrapolation of how the LDT Final Rule will apply to digital pathology requires some conjecture based on the current regulatory approach for digital pathology tools.

The Final Rule does not require that laboratories stop performing LDTs during the Phaseout period. However, if the digital pathology system used by a laboratories would be considered an LDT (e.g., internally validated as an end-to-end system under CLIA regulations), the laboratory may need to bring the system into compliance with the applicable Final Rule requirements in accordance with the Phaseout timeline.

Based on the Final Rule, an LDT that was marketed prior to May 6, 2024 (see Table in Q5/A5) may be able to remain under enforcement discretion beyond the Phaseout period, as long as the system remains unmodified or minimally modified and certain Phaseout Stages are met.

The preamble to FDA’s Final Rule does not directly address digital pathology tools. Therefore, extrapolation of how the LDT Final Rule will apply to digital pathology requires some conjecture based on the current regulatory approach for digital pathology tools.

The Final Rule does not prohibit laboratories from introducing new LDTs during the Phaseout period, as long as the requirements for each Stage are met by the compliance deadline (see Table in Q7/A7). Adigital pathology system whose components have not all been cleared by FDA for use together as an end-to-end system may be considered an LDT. If an LDT is introduced during the Phaseout period, it would not be eligible for the enforcement discretion applicable to currently marketed LDTs (i.e., LDTs first offered by the laboratory prior to May 6, 2024), but may be eligible for other categories of enforcement discretion depending on the type of LDT or test setting. If not eligible for another category of enforcement discretion, LDTs introduced after May 6, 2024 will be subject to all Phaseout Stages.

If a newly introduced LDT requires premarket authorization, the laboratory can begin performing the new LDT before Stages 4 or 5 (depending on which is applicable) and continue while the laboratory’s application for clearance or approval is under review by FDA, so long as the laboratory submits its application within the applicable timeframe.

The preamble to FDA’s Final Rule does not directly address digital pathology tools. Therefore, extrapolation of how the LDT Final Rule will apply to digital pathology requires some conjecture based on the current regulatory approach for digital pathology tools.

It depends per assumptions about the Final Rule interpretation. The LDT Final Rule states that a laboratory that modifies an FDA cleared test manufactured by a third party (e.g., commercial IVD manufacturer) may be subject to premarket review requirements depending on the type of modification. FDA “generally does not intend” to enforce premarket review requirements if a CLIA high-complexity laboratory modifies another manufacturer’s 510(k) cleared or De Novo authorized test (but not PMA approved) in accordance with design controls and other applicable quality system requirements in a manner that “could not significantly affect” the test’s safety and that does not “constitute a major change or modification” to the intended use of the manufacturer’s test, and the modified test is performed solely in that laboratory.[1] Similarly, certain limited changes to LDTs first marketed prior to May 6, 2024, can be made consistent with the enforcement discretion policy for currently marketed LDTs, which excludes premarket review.

However, the LDT Final Rule does not provide guidance on what specific changes could “significantly affect” test safety or constitute a “major change or modification” and therefore trigger the need for premarketauthorization. This is an area where additional clarification from FDA will be important.

Yes. The Final Rule states that laboratories can continue to use RUO-labeled products as components of LDTs. For those laboratories that will be subject to quality system requirements, the laboratory will need to “appropriately manage the quality” of the RUO-labeled components under its quality system.”[1] This may require, for example, that the laboratory validate such RUO components for the clinical use in accordance with purchasing control requirements (21 CFR 820.50).[2] If the LDT is subject to premarket authorization, FDA will review the use of  RUO-labeled components as part of the  premarket submission.

A laboratory performing LDTs must be in compliance with the following medical device requirements by May 6, 2025:

Medical Device Reporting

Medical device reporting is a means by which FDA monitors device performance and detects potential device-related safety issues once a device is on the market.

The Medical Device Reporting (MDR) regulation requires medical device manufacturers to establish a system that ensures the prompt identification, timely investigation, reporting, documentation, and filing of device-related death, serious injury, and malfunction information.

Complaint handling

FDA’s Quality System Regulation (QSR) for medical devices requires manufacturers to implement procedures for receiving and evaluating complaints and assessing whether they trigger MDR reporting and/or correction, removal and recall requirements. Although laboratories do not need to comply with most elements of QSR until Stage 3, complaint handling must be in place by Stage 1.  FDA regulations define a complaint as any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution.[1]

Device manufacturers must establish and maintain procedures for receiving, reviewing, and evaluating complaints and must ensure that all complaints are processed in a uniform and timely manner.  Oral complaints must be documented upon receipt. Complaints must be evaluated to determine whether a medical device report must be submitted to FDA.

In a compliance guide issued by FDA in June 2024 for clinical laboratories performing LDTs, FDA recommended that laboratories review existing guidance documents to gain insight on how to implement these requirements.[2]  However, the guidance documents referenced by FDA were developed for traditional device manufacturers and in some cases it is unclear how to adapt them to the laboratory environment, which differs from traditional IVD manufacturers in several respects.  To the extent there is overlap with CLIA requirements, laboratories may be able to leverage existing procedures to meet these new regulations.

Corrections, Removal, and Recalls 

Manufacturers of medical devices must maintain records of all “corrections” and “removals” related to their devices and in certain cases submit reports of corrections and removals to FDA. 

FDA regulations define these terms as follows:

Correction: means the repair, modification, adjustment, relabeling, destruction, or inspection (including patient monitoring) of a device without its physical removal from its point of use to some other location.[3]

Removal: means the physical removal of a device from its point of use to some other location for repair, modification, adjustment, relabeling, destruction, or inspection.[4]

A written report of a correction or removal of a device generally must be submitted to FDA by a device manufacturer if such action was initiated:

• to reduce a risk to health posed by the device; or
• to remedy a violation of the FD&C Act caused by the device which may present a risk to health.[5]

The DPA will update these FAQs on compliance with Stages 2-5 as FDA provides more detail on how laboratories will be expected to comply.