Toxicologic Pathology Forum: Opinion on Digital Primary Read and Peer Review—Diving Head-First Into the Deep Digital Pool!

Abstract

Before the COVID-19 pandemic, digital pathology was increasingly used in veterinary education, diagnostics, and research. The pandemic accelerated this adoption as institutions needed to maintain operations amidst lockdowns. It also enabled pharmaceutical companies to conduct peer reviews digitally, circumventing travel restrictions. At the 2023 Society of Toxicologic Pathology Annual Symposium, a Town Hall Meeting highlighted the current use of digital pathology. A majority of the respondents viewed whole slide images (WSI) favorably. Many institutions use digital pathology primarily for non-GLP and GLP conforming primary reads and peer reviews. Takeda has long utilized digital pathology, incorporating scanners and an image management repository, and recently adopted a cloud-based platform tailored for toxicologic pathology, enhancing efficiency and collaboration. Digital pathology not only saves time but also reduces travel needs and environmental impact. Technological advancements and wider adoption are expected to further enhance the field, promising significant benefits for the overall digital pathology infrastructure.

This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the author. It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.

Many in the veterinary pathology community had adopted digital pathology for applications in education, diagnostic service, and research ¹ (including drug discovery and development ⁵ ) prior to the coronavirus disease (COVID-19) pandemic. In response to the lockdowns that ensued at the start of the pandemic, digital pathology was more widely adopted by institutions with the existing technology, whereas others were forced to acquire the technology to adapt to operational challenges to minimize disruption to veterinary student and resident training, diagnostic service, and research. ¹⁰ In addition, travel restrictions precluded trekking to contract research organization (CRO) partners for onsite peer review of nonclinical studies via glass slides, so digital peer review was adopted by many pharmaceutical companies.

The current state of utilizing digital pathology for peer review was the topic of the Town Hall Meeting at the 2023 Society of Toxicologic Pathology Annual Symposium. Audience members were surveyed using a live polling app about their use of digital pathology. Brief presentations followed on the benefits for and reasons against adopting digital pathology as well as applicable regulatory guidance. ⁸ The session concluded with facilitated discussion related to questions and comments from audience members who may or may not have responded to the live polling.

Sixty-four percent of the 2023 Town Hall respondents surveyed indicated that their personal opinions regarding the use of whole slide images (WSI) at the current time with the current technology were favorable, and 71% reported that their institutions’ perspectives were also favorable. In ranked order, respondents shared that their institutions use digital pathology for non–GLP (Good Laboratory Practice)-conforming primary read and/or peer review, followed by GLP conforming peer review, and GLP conforming primary read and peer review. Fifty-two percent of respondents indicated that they spend ≥10% of their time evaluating WSI, including 18% spending 10% to 25% of their time, 10% spending 25% to 50% of their time, 11% spending 50% to 75% of their time, and 13% spending >75% of their time evaluating WSI. Most respondents (26%) expressed that the main reason they used WSI was for peer review, followed by consultation (19%), primary read (16%), academic or research purposes (16%), or image production (15%), with the remainder (8%) indicating they do not use digital pathology.

This opinion article summarizes the benefits of adopting digital pathology for primary read and peer review as presented at the Town Hall meeting, many of which were echoed by Town Hall survey respondents, and serves as a counterpoint to the more cautious perspective delivered by Dr Kenneth Schafer and the companion article by him and Dr Deepa Rao. ⁷

Many toxicologic pathologists, including those of us at Takeda, extol digital pathology for peer review, citing the equivalence of diagnostic utility compared with glass slides ² and improved quality and efficiency of the peer review process. However, there is no “one-size-fits-all” scenario for institutions choosing to adopt digital pathology. For many years now, Takeda has utilized multiple brightfield and fluorescent slide scanners for digitization of glass slides and a collaborative image management repository for viewing images and associated metadata and image capture. However, this repository is not currently interfaced with the application we use to manage the in-life and pathology phases of our internal non–GLP-conforming rodent nonclinical studies. In addition, the image management repository is utilized by other laboratory groups at Takeda, necessitating consensus on the metadata fields applied, and these metadata fields cannot be readily hidden for masked target organ review. Consequently, we procured a commercially available, cloud-based platform (Patholytix Preclinical, Deciphex, Chicago, Illinois; subsequently referred to as the digital pathology distribution platform) designed to specifically meet the needs of toxicologic pathologists assessing nonclinical studies with the flexibility to integrate with a study management system as well as accommodate multisite collaborations, either internally or with CRO partners. The benefits of digital pathology for primary read and peer review presented at the Town Hall meeting and herein are based on this digital pathology distribution platform which requires minimal training.

Jim Rohn said “Time is more valuable than money. You can get more money, but you cannot get more time.” The number of hours so many of us have lost over the years through the process to pack, ship, unpack, inventory, sort/organize, and re-pack boxes of glass slides is unfathomable! Although the time required to download a given study is dependent on the study size and Internet speed, the download process can be initiated so that it occurs overnight or over the weekend. It is then quick and easy to confirm that all images have downloaded and are viewable. Integration with a study management system provides for concurrent visualization of preferred metadata parameters and input and/or viewing of diagnoses. Annotation features are available to document lesion severity and facilitate consensus discussions. Target organ review or confirmation of findings for multiple animals concurrently, both informed and masked, is far more efficient than alternating single glass slides on and off a traditional microscope stage. Capture of representative images for presentations or consultation with subject matter experts is also effortless. Taken together, the digital pathology distribution platform vendor reported an overall 42% time savings using a fit-for purpose digital slide viewer vs a traditional light microscope for a simulated nonclinical review, and a large CRO partner anticipated a 30% increase in pathologist throughput globally. ⁶

Workstation components may vary between companies, but a gaming laptop with high-resolution display and an external hard drive make for a flexible “office.” Utilization of the web-based “Point-of-Use Quality Assurance (POUQA) for Pathology” tool for remote assessment of viewing conditions for reporting digital pathology slides is highly recommended. ⁹ The test requires visual discrimination between colors derived from hematoxylin and eosin staining, with a perceptual difference of ±1 delta E (dE) to address the issue of variation in display screen equipment and environment factors such as lighting for digital pathology assessment. An ambidextrous, compact 3D joystick (SpaceMouse, 3Dconnexion, Munich, Germany) and USB keypad (XK-24m, X-Keys, Williamston, Michigan) are compatible peripherals provided and specifically customized (keypad) by the vendor for use with the digital pathology distribution platform to increase efficiency, speed, and ergonomics.

We at Takeda have committed not only to digital peer reviews but also digital primary reads by our CRO partners when possible. The digital pathology distribution platform offers flexibility with regard to the assignment of preferred pathologists, independent of site. It also enhances collaboration between primary and peer review pathologists for early alignment on the nomenclature of identified findings.

The intended use of the digital pathology infrastructure necessitates consultation with in-house quality assurance personnel who may require validation of some or all components.^3,6 A GLP compliance module is available for the digital pathology distribution platform, which permits archival of GLP studies that have been “locked” upon completion of the peer review. The WSI and metadata may be exported to GxP compliant cloud or physical storage for retrieval and reconstruction of the events and conclusions of the GLP study evaluation if required.

The benefits of adopting digital pathology and the distribution platform extend beyond the peer review. The WSI and metadata are rapidly retrievable for subsequent training, drug project awareness, development of artificial intelligence algorithms, and data mining.

As noted above, adopting digital pathology alleviates the need to travel to other company sites or CRO partners. Although this favorably impacts budgets by removing travel expenses, it also benefits the environment through reduced carbon emissions. On a personal level, removing the travel requirement associated with a peer review enables pathologists to attend to other professional responsibilities and personal commitments during the week they are scheduled to review WSI. In addition, digital pathology alleviates the need to obtain permits from the Convention on International Trade in Endangered Species (CITES) for the shipment of slides from studies involving nonhuman primates or any endangered species. Significant timeline delays, such as those associated with the exporter obtaining the permit, a process which can take 3 to 6 months, and clearing Customs, can be avoided.

We are in the midst of the digital pathology revolution, and it is transforming diagnostics, education, and research, including drug discovery and development! Many are resistant to change, especially disruptive change. Technology associated with digital pathology has continued to evolve since the first commercial slide scanner was designed in 1994. ⁴ Hardware such as scanners and displays, software including digital pathology distribution platforms, their integrations with collaborative image management repositories, nonclinical study management systems, and image archival options would all have remained stagnant were it not for collaborative feedback and suggestions for improvement from early adopters of digital pathology. Technological advances combined with adoption by increased numbers of institutions and individuals will continue to drive down costs and enhance the overall digital pathology infrastructure. We at Takeda have chosen to dive into the deep end of the digital pool head-first, and we invite you to join us!