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Toxicologic/veterinary pathologists are working remotely from Good Laboratory Practice (GLP) test facilities (TFs) in increasing numbers, most commonly in home-office settings. A study pathologist (SP) generating data on GLP-compliant nonclinical studies must be keenly aware of applicable national GLP regulations and comply with TF and protocol requirements. This Toxicological Pathology Forum Opinion Piece will summarize primary areas of emphasis for the SP generating GLP data using glass slides. Peer review and digital review of whole slide images are out of scope for this opinion piece. Key GLP considerations for primary pathology on glass slides are discussed with respect to SP location and employment status, including pathologist qualifications, specimen management, facilities, equipment, archive, and quality assurance. Notable differences between national GLP regulations of the United States, the United Kingdom, Germany, the Netherlands, France, Ireland, Switzerland, Italy, and Israel are presented. With the understanding that each combination of location and employment is unique, the authors provide a general overview of considerations for successful remote GLP work.

The advancement of an investigational new drug in humans is a significant developmental milestone. In first-in-human (FIH)-enabling toxicology studies, the highest dose without a test article-related adverse effect (no-observed-adverse-effect-level [NOAEL]) serves as the basis for deriving a safe FIH starting dose. For anticancer pharmaceuticals, the FIH dose may be calculated using the highest non-severely toxic dose (HNSTD) in nonrodent models or the dose severely toxic to 10% (STD 10 ) in rodents. Given the practice of reporting the NOAEL, but the lack of regulatory requirements to do so for anticancer pharmaceuticals, we conducted an informal survey of 20 companies to answer the question "How is our industry reporting toxic/adverse dose levels in FIH-enabling toxicology studies for anticancer indications?" The data indicated 4 reporting approaches, each providing a path to regulatory acceptance. Within the integrated toxicology study report, 45% of respondents report the HNSTD/STD 10 , 25% report the NOAEL, 20% report both the HNSTD/STD 10 and NOAEL, and 10% do not define either, reserving definitions for regulatory submissions. One reporting approach may be preferred over another for reasons including consistency across indications, repurposing pharmaceuticals, regulatory feedback, or simplicity. The reporting approach should be defined in advance of study initiation, and the pathologist should provide context to support the chosen approach.

Nonclinical toxicology studies that are required to support human clinical trials of new drug candidates are generally conducted in a rodent and a non-rodent species. These studies typically contain a vehicle control group and low, intermediate, and high dose test article groups. In addition, a dosing-free recovery phase is sometimes included to determine reversibility of potential toxicities observed during the dosing phase and may include additional animals in the vehicle control and one or more dose groups. Typically, reversibility is determined by comparing the test article-related changes in the dosing phase animals to concurrent recovery phase animals at the same dose level. Therefore, for interpretation of reversibility, it is not always essential to euthanize the recovery vehicle control animals. In the absence of recovery vehicle control tissues, the pathologist's experience, historical control database, digital or glass slide repositories, or literature can be used to interpret the findings in the context of background pathology of the species/strain/age. Therefore, in most studies, the default approach could be not to euthanize recovery vehicle control animals. This article provides opinions on scenarios that may or may not necessitate euthanasia of recovery phase vehicle control animals in nonclinical toxicology studies involving dogs and nonhuman primates.

The IQ Consortium NHP Reuse Working Group (WG) comprises members from 15 pharmaceutical and biotechnology companies. In 2020, the WG developed and distributed a detailed questionnaire on protein non-naïve NHP reuse to the WG member companies. The WG received responses from key stakeholders including principal investigators, facility managers, animal welfare officers and research scientists. This paper's content reflects the consolidated opinion of the WG members and the questionnaire responses on the subject of NHP reuse within nonclinical programs at all stages of research and development. Many of the pharmaceutical companies represented in the working group or participating in the questionnaire have already achieved some level of NHP reuse in their nonclinical programs, but the survey results suggested that there is significant potential to increase NHP reuse further and a need to understand the considerations involved in reuse more clearly. The WG has also focused carefully on the inherent concerns and risks of implementing protein non-naive NHP reuse and has evaluated the best methods of risk assessment and decision-making. This paper presents a discussion on the challenges and opportunities surrounding protein non-naïve NHP reuse and aims to stimulate further industry dialogue on the subject and provide guidance for pharmaceutical companies to establish roadmaps and decision trees enabling increased protein non-naïve NHP reuse. In addition, this paper represents a solid basis for collaborative engagement between pharmaceutical and biotechnology companies with contract research organizations (CROs) to discuss how the availability of protein non-naïve NHP within CROs can be better leveraged for their use within nonclinical studies.

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.

Pathologists are trained medical professionals with special expertise in diagnostics, research, and pathophysiology. In these roles, pathologists are well qualified and positioned to engage in conversations about animal use replacement, reduction, and refinement (3Rs), thereby championing the guiding principles of the 3Rs. In particular, toxicology or nonclinical safety assessment is an important area where the discipline of toxicologic pathology can have a critical role in adopting 3Rs principles. As such, a working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee was formed to investigate and summarize some of the areas where veterinary pathologists working in the field of toxicology can increase involvement and impact on 3Rs. This "Points to Consider" publication provides an overview of areas within toxicology where the veterinary pathologist's perspective may maximize animal value, including refinement of study design, optimizing sample collection, the development of 3Rs focused regulatory policy, and humane end point determination.[Box: see text].

The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should be assigned based only on the extent (i.e., amount and complexity) of the morphologic change in the examined tissue section(s) and be clearly defined in the pathology report for critical lesions impacting study interpretation. However, the level of detail provided and criteria by which severity grades are assigned can vary, which can lead to inappropriate comparisons and confusion when evaluating pathology results. To help address this issue, a Working Group of the Society of Toxicologic Pathology's Scientific and Regulatory Policy Committee was formed to provide a "points to consider" article on the assignment and application of pathology severity grades. Overall, the Working Group supports greater transparency and consistency in the reporting of grading scales and provides recommendations to improve selection of diagnoses requiring more detailed severity criteria. This information should enhance the overall understanding by toxicologic pathologists, toxicologists, and regulatory reviewers of pathology findings and thereby improve effective communication in regulatory submissions.

In July 2015, the U.S. Food and Drug Administration (FDA) posted a new draft guidance entitled "Testicular Toxicity: Evaluation during Drug Development Guidance for Industry," with a 90-day public comment period. As the nonclinical assessment of testicular toxicity often relies on the expert interpretation of pathology affecting the male reproductive tract, this draft guidance is considered directly relevant to the toxicologic pathology community. Therefore, a working group was formed through the Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathologists (STPs) to provide a detailed review of the draft guidance. Specific comments on the guidance were submitted to the FDA by the STP. The draft guidance and all comments received are currently under review with the FDA. This commentary provides a summary of the components of the draft guidance and the comments submitted by the STP with acknowledgment of different perspectives reflected in comments from other respondents., (© The Author(s) 2016.)

The U.S. Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a multitiered approach to determine the potential for environmental chemicals to alter the endocrine system. The Pubertal Development and Thyroid Function in Intact Juvenile/Peripubertal Female and Male Rats (OPPTS 890.1450, 890.1500) are 2 of the 9 EDSP tier 1 test Guidelines, which assess upstream mechanistic pathways along with downstream morphological end points including histological evaluation of the kidneys, thyroid, and select male/female reproductive tissues (ovaries, uterus, testes, and epididymides). These assays are part of a battery of in vivo and in vitro screens used for initial detection of test article endocrine activity. In this Points to Consider article, we describe tissue processing, evaluation, and nomenclature to aid in standardization of assay results across laboratories. Pubertal assay end points addressed include organ weights, estrous cyclicity, clinical pathology, hormonal assays, and histological evaluation. Potential treatment-related findings that may indicate endocrine disruption are reviewed. Additional tissues that may be useful in assessment of endocrine disruption (vagina, mammary glands, and liver) are discussed. This Points to Consider article is intended to provide information for evaluating peripubertal tissues within the context of individual assay end points, the overall pubertal assay, and tier I assays of the EDSP program., (© 2015 by The Author(s).)

Increased cell proliferation is a central key event in the mode of action for many non-genotoxic carcinogens, and quantitative cell proliferation data play an important role in the cancer risk assessment of many pharmaceutical and environmental compounds. Currently, there is limited unified information on assay standards, reference values, targeted applications, study design issues, and quality control considerations for proliferation data. Here, we review issues in measuring cell proliferation indices, considerations for targeted studies, and applications within current risk assessment frameworks. As the regulatory environment moves toward more prospective evaluations based on quantitative pathway-based models, standardization of proliferation assays will become an increasingly important part of cancer risk assessment. To help address this development, we also discuss the potential role for proliferation data as a component of alternative carcinogenicity testing models. This information should improve consistency of cell proliferation methods and increase efficiency of targeted testing strategies., (© 2015 by The Author(s).)

The systemic inflammatory response syndrome (SIRS) is a clinicopathological manifestation of overexuberant acute-phase inflammation caused by infectious or noninfectious etiologies. The systemic release of pro-inflammatory cytokines, chemokines, and lipid and vasoactive mediators induces endothelial damage and microvascular thrombosis, potentially culminating in disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and multiple organ dysfunction (MOD) or failure (MOF). We present five cases in the pig-tailed macaque and olive baboon where SIRS resulted in MOF, ARDS, DIC, and the Waterhouse-Friderichsen syndrome; each with gross and histological elements manifested as edema, deposition of fibrin, hemorrhage, and thrombosis. In the described cases, SIRS was the end-common pathway for multiple risk factors that parallel those documented in humans: major surgery, obstetric complications, and infection. The diagnosis of SIRS should be considered when evaluating nonhuman primate (NHP) cases of MOF manifesting with histological evidence of vascular leakage. Experimental manipulation of NHP models may be complicated by SIRS and accompanying rapid clinical decompensation. Such adverse events may compromise toxicological studies and should be avoided when possible.