Abstract
The coronavirus disease 2019 pandemic has affected business on numerous fronts in unprecedented and abrupt ways. From site closures and local “stay-at-home orders” to travel advisories and restrictions, the day-to-day practice of toxicologic pathology has been impacted dramatically and rapidly. A critical function of Toxicologic Pathologists is performing pathology peer review for nonclinical studies. Traditionally, corroborating the findings of histological assessment could be achieved through shipment of histopathological slides to the peer review pathologist, or by the peer review pathologist traveling to the location of the slides (eg, the test facility). Since early 2020, many pathologists have been unable to perform the latter due to local, regional, national, test facility, company, and/or personal restrictions. The disruption for some has been minimal, while others are working from home for the first time. We recommend that contingency plans for all peer review procedures and personnel should be in-place to accommodate sudden and unexpected workflow transitions. Now, more than ever, approaching peer reviews with enhanced adaptability will help ensure success.
Keywords
Background
Pathology peer review is the process of obtaining a second opinion to confirm and potentially improve diagnoses and interpretations generated by a study pathologist. Peer review is a component of most good laboratory practice (GLP) studies and is recommended when important risk assessment or business decisions are based on nonclinical studies. 1 Peer review for nonclinical studies is most commonly prospective and can be accomplished through 4 general approaches. The first approach is the simplest and consists of delivering histopathology tissue sections, hereinafter referred to as slides, “down the hall” to the peer review pathologist if the study and peer review pathologists work at the same location. Where the study and peer review pathologists are in different locations, slides may be transferred between the 2 locations (second approach). Traditional advantages of shipping slides to the peer review pathologist include flexibility for the peer review pathologist (schedule and location), access to personal references/equipment, and the potential opportunity for collaboration within an intraorganizational team. A third approach is for the peer review pathologist to “come to the slides” by traveling to the test site, test facility, laboratory, or contract research organization (CRO) responsible for data integrity. Benefits of the peer review pathologist traveling to the slides may include an expedited timeline, less chain-of-custody procedure, and/or the opportunity to meet face-to-face with the study pathologist. A fourth, less traditional approach is the review of whole slide images from scanned slides, which is gaining traction as it becomes more technologically feasible and acceptable. Because each approach has advantages and disadvantages, companies select the approach(es) that meet their unique needs and capabilities. Variables that influence selection of the pathology peer review approach include the business model of the study sponsor (ie, fully [or vertically] integrated pharmaceutical company vs fully integrated pharmaceutical network and in between), timeline requirements, study design, expected complexity of pathology findings, experience of the pathologists (study and peer review), ability of the slide location (hereafter referred to as the CRO) to accommodate on-site peer reviews, digital technological capabilities, and expected costs. Prior to the pandemic, most sponsors used a hybrid approach to peer review where slides were shipped for some studies and the peer review pathologist traveled for other studies.
Challenges Presented by Pandemic Conditions
During the global coronavirus disease 2019 (COVID-19) pandemic, the practice of peer review has changed for many Toxicologic Pathologists with uncertainty as to when, or if, previous workflows will return. Some recent challenges faced by pathologists included: Inability for the peer review pathologist to travel: Workflows that include peer review pathologist travel were disrupted as countries and companies instituted travel bans. Limited or complete lack of access to peer review sites: Workflows that included peer review at the CRO were limited by newly instituted visitor policies designed to ensure business continuity and protect the health and safety of essential CRO employees. Inability to work at local offices: Within regional COVID-19 hot spots, “stay-at-home orders” and temporary site closures further disrupted usual workflows.
In response, the work environment became home based for many pathologists. Working from home, unexpectedly, during a pandemic presented unique challenges including:
Ensuring adequate home office infrastructure (eg, furniture, microscope, network connectivity or bandwidth, or ergonomic set up).
Ensuring adequate procedures for slide receipt and shipping.
Ensuring workspace free of interference from family members, partners, and children, while balancing remote working and learning.
Addressing logistical challenges due to illnesses or quarantine of key personnel assigned to studies, including the peer review or study pathologists.
Managing changes in study timelines due to delays or suspension of shipments, including slides.
Impact of Challenges
The COVID-19 pandemic is having a variable impact, sometimes significant, on the practice of pathology peer review. In many organizations, the majority of personnel who can conduct work off-site have been asked to do so, and as a result, adjustments have been made by our industry. For pathologists who were conducting peer reviews remotely prior to the pandemic, little has changed. However, for those traditionally traveling to CROs, much has changed. Here, we discuss the impact of the recent challenges listed above.
Peer reviews previously planned at a CRO needed to be performed at alternative sites
When peer review was shifted away from a CRO to an established corporate office space, peer review pathologists and managers were faced with creating a productive and safe environment. At the time of this writing, most organizations have limited numbers of on-site staff and have implemented heightened processes for hygiene, sanitization, and social distancing. For larger organizations, programs for scheduling and tracking the location of staff and contractors are in place to monitor population density in the workplace and facilitate the potential need for contact tracing.
When peer review was shifted away from a CRO to a home office, those unfamiliar with working from home faced a steep learning curve. Minimally, a pathologist requires a dedicated ergonomic workspace complete with office equipment needed to conduct business. It cannot be overlooked that for many, home may not be outfitted with sufficient workspace, a microscope, material supplies (eg, printer/scanner), sufficient internet bandwidth, and low noise levels. Further, some pathologists may be competing with ongoing children’s activities at home that are related to “e-learning.” Importantly, home peer review may require the peer review pathologist to take on the shipping and receiving practices, which are traditionally performed by others. Although this commentary is not focused on GLP compliance of pathology peer review, compliance is important to take into consideration if an organization plans modifications to their approach to pathology peer review. Compliance practices vary based on corporate risk aversion and quality assurance expectations. Organizations may want to consider whether standard operating procedures or other policies are in place to, at a minimum, layout procedures for the security and chain-of-custody for slides (to receive, inventory, maintain, and return slides).
When peer reviews were shifted away from a CRO, there may have been difficulty in handling some study types. For example, shipping slides for large studies present inherent challenges; most notably, 2-year carcinogenicity studies which may have more than 20,000 slides. Technical considerations must be considered in advance, including physical space, batch shipment of early termination animals to the sponsor’s peer review pathologist, or outsourcing the peer review to a pathologist located at the CRO facility with sponsor consultation as appropriate and necessary. In such circumstances, detailed mitigation planning and close communication between partners is required far in advance of study termination to ensure successful outcomes.
Moving forward, CRO partners are developing study monitoring services to help clients meet their oversight needs assuming pandemic-related travel restrictions. These offerings will be critical for peer review pathologists who traditionally monitored complex or critical necropsies or are assigned as the peer review pathologist for continuity. On a larger scope, some CROs are in the process of accommodating requests for virtual client and regulatory audits, site tours, and study monitoring while utilizing cross-functional teams, including animal welfare, legal, information technology, security, facilities, and marketing, to ensure the solutions adequately balance risk and opportunity.
Remote review required shipping and an adjustment to timelines
Depending upon shipping arrangements (on-site peer review pathologist pickup, local courier, shipping via secured mail, or sending by courier across the country), consideration should be given to incorporating transfer time into the study timelines. These are likely to be on average 1 to 2 days on each end but may be longer if international shipments are involved. Material transfer delays may still happen but can sometimes be mitigated or offset in the overall study timeline particularly with high priority studies. Because pathology results are usually one of the last set of data needed in preparation of the final toxicology report, an unexpected delay in peer review can negatively impact business-critical timelines and subsequent program progression or regulatory filing. Earlier in the pandemic, there was concern regarding shipped materials (eg, paperwork, slides, slide boxes, shipment packaging) as potential fomites. Practices such as latency periods for delivered materials (assuming study timelines allowed), disinfecting shipping boxes, and gloved slide reading were suggested. However, recent publications have allayed the concern for infection spread through such materials due to transit time of contents and/or virus survival time on various surfaces. 2 –5
In this age of globalized business, many studies are performed across borders. International shipment of slides from nonhuman primate (NHP) studies requires Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) permits. Timelines for obtaining CITES permits can be a significant impediment if not planned a priori. Proactively working with CRO partners and establishing procedures for unique circumstances can help mitigate this potential complication. However, with the rapid development of the pandemic and change in business practices, international shipment of NHP tissues did complicate many studies.
In addition to timeline revisions necessary to accommodate slide shipping, in some instances, strains on traditional supply chains have affected study initiation. For some organizations, COVID-19 vaccine research has been prioritized over all other projects. More broadly, test article production or shipping delays due to manufacturing closures or supply chain interruptions have also been reported. Although initial supply chain challenges have largely been resolved, there is still concern over NHP availability due to increased demand, extended periods of quarantine at animal origin, and export bans. These uncontrollable and unpredictable strains on supply chains resulted in fluid, delayed, or uncertain study timelines, which will have downstream scheduling consequences for all stages of drug development.
Remote peer reviews resulted in the need to achieve consensus virtually
Because peer review for any study is an iterative process, effective communication is of utmost importance in achieving consensus, especially when findings are complex. Technology including videoconferencing, interactive slide or photomicrograph viewing, and whole slide scanning can help facilitate virtual conversations. These remote technologies are helpful with slide evaluation but also to enable effective engagement for colleagues, customers, regulators, and auditors. Video technology is being utilized for face-to-face meetings to strengthen connectivity, engagement, and collaboration across locations, business units, and geographies. In fact, depending on one’s work situation prior to the pandemic, he or she may feel even more connected now than ever before thanks to these collaborative technologies. To support the expanded use of live streaming, extra virtual private network connections for faster internet connectivity and secure online access to electronic data and reporting systems have been implemented in many organizations. However, the use of these video technologies assumes that either the slides have been previously scanned to whole slide images or, if not scanned, that both the study and peer review pathologists have digital cameras on their microscopes to facilitate discussion of findings. Further, remote technologies cannot always alleviate the difficulties in assessing subtle lesions where a pathologist desires to review specific target tissues in a masked manner. Such an approach is easy with glass slides but is more difficult with digital slides. For remote peer review of subtle lesions and resolution of difficult interpretations, slides may need to be shipped back and forth to reach consensus.
Hiring of local third parties to perform pathology peer review
Contract research organization partners fielded last-minute requests and worked to develop innovative methods to accommodate virtual oversight. When a peer review pathologist was not allowed to travel, or slides could not cross international borders in a timely manner, an additional pathologist at the CRO or an independent pathologist located nearby was contracted to perform peer review.
Lessons Learned
The COVID-19 pandemic has presented learning opportunities on how to conduct pathology peer reviews using innovative, likely sustainable, methods. These workflow modifications will be implemented indefinitely and ideally, with flexibility and frequent reassessment to meet current demands. Continual improvement of workflows will help address future demands. It is important to recognize that a challenge met with resilience, and a practical degree of accommodation paves the way for developmental opportunities and evolution. The following are key lessons learned thus far:
Now, more than ever, approaching peer reviews with enhanced adaptability will help ensure success: Peer reviews have historically been a cooperative venture. As always, quality of the pathology interpretation as well as timely completion will depend on judicious planning and excellent communication. Exercising flexibility within reason and utilizing available technologies to supplement challenges posed by work environments and distance are critical to success now and in the future. Minimally, all pathologists participating in peer reviews should have a microscope equipped with a camera and appropriate computer equipment at their home office. The potential benefits of supplying pathologists with these core tools go beyond the confines of the peer review itself and include consultation with internal subject matter experts when deemed beneficial for a challenging study.
Continued acceptance and expanded use of digital pathology technology on varying levels (eg, microscope cameras, select whole slide imaging, whole study digital peer reviews) will be transformative to the way peer review is conducted: Interestingly, the increased attention to and practice of digital peer review is unrelated to the current pandemic, but its practice and acceptance may be expedited as a result. Some companies are already implementing this technology, while others are investigating the process and associated investment related to staff, space, and finances. When considering study timelines, it is important to realize the increased pressure that digital pathology tools or platforms will place on information technology infrastructure, which is already strained by the transition to remote working arrangements.
Contingency plans for all peer review procedures and personnel should be in-place to accommodate sudden and unexpected workflow transitions: Factors to consider when enhancing a given organization’s plan with respect to peer review include those related to technical and administrative aspects such as slide shipment/receipt, scanning, scheduling, study-specific factors (eg, animal and formulation availability), and pathology expertise. Specific to this latter component, establishing a relationship and service agreement with a third-party consulting pathologist (ideally, at or near the test site) may be essential for organizations with limited numbers of pathologists, especially when unanticipated events (eg, sickness, study-specific factors) arise and in-house reassignment of the peer review responsibility cannot be accommodated. Similarly, developing relationships with multiple pathologists at international test facilities will facilitate communication and help ameliorate the burden of protocol-driven modifications when it is necessary to outsource a peer review to a second CRO pathologist.
Organizations that outsource their nonclinical toxicity studies may need to carefully plan the location of the CRO where their studies will be placed in order to avoid the complications secondary to restrictions on travel or on shipping of animals, slides, test articles, or other materials.
Conclusion
The COVID-19 pandemic is having a variable, sometimes significant, impact on the practice of pathology peer review. Consistent with local, national, and global public health requirements, our professional community is adapting work practices to reduce exposure to the risks caused by the COVID-19 pandemic. Organizations adapted and continued operating in sometimes innovative ways. How and where we perform critical functions including peer-review has become fluid by necessity. Although remote peer review may not have been the preferred option for some studies, it has been shown to be practical, and sometimes preferable under the current conditions. With or without this pandemic, the established practice of pathology peer review will continue to evolve as digital image sharing and communication technologies progress. With the unknown duration of pandemic-associated challenges, and uncertainty of what the new “normal” will ultimately be, prudent review and refinement of peer review approaches and workflows will be necessary for the foreseeable future.
Footnotes
This is a commentary article submitted to the Toxicologic Pathology Forum. It represents the views of the authors. 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.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
References
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