2025 International Academy of Toxicologic Pathology (IATP) Satellite Symposium: Pathology Working Groups (PWGs) in Toxicologic Pathology

Pathology Working Groups (PWGs) are specialized panels of expert pathologists convened to provide independent, unbiased assessments of specific questions that arise during pathology peer review or are presented by regulatory authorities. Pathology Working Groups play a crucial role in establishing appropriate nomenclature and diagnostic criteria for pathological findings of interest or novel findings, as well as addressing issues that may result in a clinical hold on candidate compounds. Pathology Working Groups are routinely conducted by the Division of Translational Toxicology, NIEHS (formerly the U.S. National Toxicology Program [NTP]) for rodent carcinogenicity studies destined to be used for environmental chemical hazard identification and risk assessment.

An International Academy of Toxicologic Pathology (IATP)-sponsored symposium at the Joint Congress of the European and British Societies of Toxicologic Pathology (ESTP/BSTP) in Manchester, UK, provided a set of presentations that described PWGs from an historical perspective and context of current applications of PWGs and Expert Working Panels (EWPs) in support of risk assessment for environmental chemicals and pharmaceuticals. For most regulated toxicology studies in support of safety assessment, quality and accuracy of the pathology data and interpretation are achieved through effective interactions between the study pathologist and the peer-reviewing pathologist. However, in those cases where unresolved questions remain, PWGs can help. These groups are composed of expert pathologists selected to answer a specific question and can also be constituted to address queries from regulatory authorities.^2,5,8

Paul Snyder from EPL Laboratories noted the inherent subjectivity of pathology and the consequent need for PWGs to provide decision-makers and regulators with the most accurate, unbiased, consensus view on pathology data. Defining a specific question for the group is critical to the process and for deriving value for the sponsor. Participants could include veterinary, medical, and experimental pathologists as needed. The PWG is a specialized type of review. Unlike routine peer review, PWGs are convened to answer specific questions regarding study results. They may be convened by study sponsors, consortiums, or government agencies. Pathology Working Groups may be conducted after a study (or studies) have been finalized and thus require full documentation. They may also be conducted prior to finalizing the study report. The typical panel for the PWG is composed of a group of expert pathologists who are assembled to discuss a specific question regarding study results. Since the purpose of the PWG is to provide an independent unbiased opinion, members of the PWG may come from academia, government, or industry. An uneven number of panel members are selected based on their experience in toxicologic pathology, as well as their expertise in the area or organ being discussed. The odd number of panelists, usually 5 or 7, is to assure a final decision when voting. Pathology Working Groups may be convened to answer any number of specific questions such as confirming tumor diagnoses or confirming severity scoring accuracy for non-neoplastic lesions.

Mark Cesta of the Division of Translational Toxicology (formerly the US National Toxicology Program) at the National Institute of Environmental Health Sciences (NIEHS) described the formal, comprehensive process which applies PWGs to all NTP-sponsored chronic bioassays. The aim is to verify the accuracy and diagnostic consistency of the toxicologically significant microscopic findings. Quality assessment and the PWG are provided by different, independent contract labs, and the PWG is conducted blinded to the treatment group. This standard approach maximized confidence in an unbiased and accurate interpretation of the study. The Division of Translational Toxicology (DTT) at the NIEHS was created out of the National Cancer Institute (NCI) Bioassay Program in 1978. The NCI Bioassay Program was established in 1962. Problems were identified with many of the bioassays in the original NCI Bioassay Program. The U.S. Government Accounting Office (GAO) identified many bioassays that were so deficient that their results could not be published. ⁴ As a result, the bioassay program was moved to NIEHS as the NTP. Pathologists at the NTP developed a peer-review system to resolve the issues that resulted in the problems identified by the GAO and ensure they were prevented in all future studies. There are four steps in the DTT (former NTP) pathology peer-review process: the audit of pathology specimens (APS), the pathology data review (PDR), the quality assessment (QA), and the PWG. In this process, all the data and materials are reviewed to ensure accuracy and consistency. The QA and PWG are performed by different contract labs, and the PWG is conducted in a blinded fashion (with the participants having no knowledge of the dose groups) to avoid bias and conflicts of interest. The goals of the PWG are to provide a consensus opinion on the toxicologically significant findings and to verify their accuracy, resolve diagnostic differences between the study pathologist and the peer review pathologist, recommend additional reviews if needed, and ensure the findings are correctly interpreted. This process ensures the accuracy of the data from NTP/DTT studies, and for the past 45 years, the pathology peer-review process used by the DTT/NTP has been considered the gold standard by regulatory agencies in the United States, Europe, and Japan.

Frederic Schorsch of Bayer Crop Sciences provided a perspective of PWG application to agrochemical development that illustrated the value of PWGs in clarifying carcinogenicity study findings. Evaluating carcinogenic potential can be complex. The chronic toxicity and carcinogenicity studies are typically the last studies for human safety evaluation conducted before an agrochemical compound is submitted for government regulatory review. Their conclusions are often critical both for identification of carcinogenic properties and for non-neoplastic adverse findings. Assessment of pathological findings must be reliable and unquestionable. It is not rare that regulatory authorities raise questions regarding the interpretation of some changes picked up among the huge amount of data generated in these studies. The final statement made in the toxicology report can be enhanced from expert pathology review and effective application of PWGs to support regulatory decision-making. ⁶ More recently, the use of digital pathology and the application of the toxicologic pathology community’s International Harmonization of Nomenclature and Diagnostic Criteria (INHAND, https://www.toxpath.org/inhand.asp#pubg) terminology project have considerably helped the efficiency and consistency for and across PWGs and their discussions on diagnostic criteria. Three present examples provided evidence of the value of a PWG for agrochemicals, illustrating how conclusions regarding potential carcinogenicity were supported. In case 1, a fungicide acting as a succinate dehydrogenase inhibitor, the PWG examined findings from a 2-year carcinogenicity study in Wistar rats. Despite some regulatory authorities suggesting a link between observed tumors and treatment, the PWG affirmed that there was no evidence of treatment-related increases in histiocytic sarcomas, brain astrocytoma, and ovarian tubulostromal neoplasms. The statement made by the panel members of the PWG confirmed the conclusion reached more than 10 years earlier by the study pathologist. In the meantime, three INHAND publications redefined the classification of the ovarian, histocytic, and brain tumors in question.^1,3,12 The originally diagnosed astrocytomas observed in the high-dose group in the brain were reclassified as Glioma, not otherwise specified (NOS) based on the most recent, new, and revised INHAND diagnostic criteria. It was the same for the ovarian tumors, for which criteria to classify tubulostromal neoplasms have evolved since the completion of the carcinogenicity study, but despite a completely new classification, the PWG panel’s interpretation was consistent with the original study, despite several differences between the original study diagnoses and the PWG panel diagnoses. The fact that a group of independent pathologists, using up-to-date classification criteria, arrived at the same interpretation of the lesions observed in the study carries significant weight for the authorities reviewing the active ingredient in question. The second case focused on an insecticide affecting the ryanodine receptor. The PWG reviewed a chronic toxicity and carcinogenicity study report that had the conclusion of an increased incidence of uterine tumors in high-dose female rats. The PWG confirmed the presence of proliferative findings in the uterus. Again, the PWG was supportive to reinforce the original statement found in the pathology report. Finally, the third PWG was convened to evaluate proliferative changes in the thymus gland observed during a 2-year rat study to test carcinogenicity of a fungicide from the thiazolyl piperidine family. The study pathologist stated that the increase in benign thymoma was not considered treatment-related, even though the incidence was found to be statistically significantly different compared to controls and outside the historical control data (HCD) at the test facility. The study pathologist’s conclusion was based on a weight of evidence evaluation and the absence of a statistical difference when hyperplastic and neoplastic thymic proliferations were combined, on the absence of difference in males, and on published data supporting a relatively high incidence of thymoma in female Wistar rats.^7,9,11 The panel unanimously concluded that the observed non-neoplastic and neoplastic findings in this organ were not related to treatment, reinforcing the absence of treatment-related carcinogenic findings. These examples exemplify the value of conducting a PWG for decision-making regarding human risk assessment in the context of agrochemical safety. The PWGs are now easier to conduct with the advances and simplification brought by modern digital pathology tools that aid in more efficient panel discussions and by the application of modern, concurrent, and consistent diagnostic criteria clearly defined within the INHAND terminology project.

Maurice Cary of Pathology Experts GmbH, Switzerland, introduced the concept of the expert working panel (EWP). This differs from a PWG in that the slides or images are not provided blinded to the expert pathologist, and the question is more likely to consider risk assessment of findings or investigative study design rather than differences in opinion on the morphological diagnoses. Furthermore, a major difference is that EWPs may also include expert toxicologists, as well as any other specialties deemed necessary to address the issues in line with the challenges faced by the sponsor. Expertise on the panel might include, in addition to toxicologic pathology and general toxicology, a range of expertise typically required for drug development and the assessment of risk, including but not limited to clinical pathology, reproductive toxicology, genetic toxicology, drug metabolism and pharmacokinetics (DMPK), project management, and regulatory experience. Emphasis was given to the critical role of the Panel Manager for whom broad experience and understanding of the entire drug development process to properly conduct an EWP are a must. A wide range of study endpoints such as clinical observations, clinical pathology, mechanism of action, outcomes of in vitro discovery studies, compound chemical structure, relevance to human safety, and test article exposure (toxicokinetics) may be considered to arrive at a conclusion. Pathology Working Groups mostly serve to resolve disagreements between the study pathologist and peer-review pathologist or to confirm findings that may be borderline statistically significant and may sometimes include mode of action, relation to treatment, and toxicological significance in the PWG report. Modified PWGs, EWPs, resolve issues for compounds that may have been placed on hold in the clinics by a regulatory agency or to facilitate internal GO/NO-GO decisions regarding the continued development of a compound. Thus, the EWP report includes some of the same points discussed in a classic PWG report but will also include discussion of the pathology finding(s) with the added perspective of significant in-life findings, exposure, and any other data deemed necessary to properly address the broader issue beyond the specific tissue response interpretation.

Following the presentations, a panel discussion was conducted with additional comments from panel members. Alys Bradley of Charles River Laboratories who stressed the importance that the PWG or EWP members have at least 5 years of experience with pathology and toxicology interpretation in the species and/or organ system used in the reviewed study to lend integrity and qualification to the consensus report. The use of Digital pathology has meant that PWGs can be conducted quickly and efficiently with little impact on study timelines to ensure good quality pathology data. Dirk Schaudien of the Fraunhofer Institute for Toxicology and Experimental Medicine emphasized that the use of the INHAND nomenclature during study reading and the peer-review process is highly important so that every involved person has the same and most current view for diagnosis of the lesions in the study. Furthermore, cases of hyperplasia borderline to neoplasia should be included in the peer-review process. To enhance this, the respective cases should clearly be diagnosed as borderline cases, eg, with a severe grade of hyperplasia.

In summary, it is clear the critical role the Pathology Working Group and Expert Working Panel can play in establishing confidence in proper and accurate evaluation of carcinogenicity studies including interpretation of data for assessing the risk of success for a new chemical or drug development project and for accurate human health risk assessment.