| INTRODUC TI ONClinical pathologists working in the industry setting provide specialized expertise in the interpretation of clinical pathology results to support nonclinical animal studies for the purposes of pharmaceutical, agrochemical, food additive, and medical device safety assessment. As the number and complexity of clinical pathology and biomarker assays used in these studies has steadily grown over the last several decades, so has the specialized discipline of Toxicologic Clinical Pathology. Test article-related (TAR) clinical pathology findings must not only be accurately reflected in an interpretive report, but they must also be integrated with other relevant study data (eg, anatomic pathology, in-life, toxicokinetic). Although the task of interpretation of clinical pathology results is sometimes assigned to individuals with little to no formal clinical pathology training, we recommend that clinical pathology interpretive reports be authored by veterinary clinical pathologists with specialized training and experience in toxicologic clinical pathology, especially for pivotal (early and late stage) nonclinical studies. The purpose of this manuscript is to present an overview of current interpretive practices within the pharmaceutical industry and to propose guidelines that will help authors draft accurate, industry-standard clinical pathology interpretive reports. | ROLE AND QUALIFI C ATI ON S OF THE CONTRIBUTING SCIENTIS TClinical pathology evaluations are an integral part of most nonclinical pharmaceutical and agrochemical research projects ranging from proof of concept to general toxicology studies, target animal safety (in the development of animal health products), and medical Abstract The interpretation of clinical pathology results from nonclinical safety studies is a fundamental component in hazard identification of new drug candidates. The everincreasing complexity of nonclinical safety studies and sophistication of modern analytical methods have made the interpretation of clinical pathology information by a highly trained subject matter expert imperative. Certain interpretive techniques are particularly effective in the identification and characterization of clinical pathology effects. The purpose of this manuscript is to provide an overview of contemporary interpretive practices for clinical pathology results and to provide nonbinding recommendations aimed at improving consistency, quality, and overall value of clinical pathology interpretations generated in support of nonclinical toxicology studies.

There is limited direction in the literature or regulatory guidance on determination of adversity for clinical pathology (CP) biomarkers in preclinical safety studies. Toxicologic clinical pathologists representing the American Society for Veterinary Clinical Pathology-Regulatory Affairs Committee and Society of Toxicologic Pathology-Clinical Pathology Interest Group identified principles, overall approach, and unique considerations for assessing adversity in CP data interpretation to provide a consensus opinion. Emphasized is the need for pathophysiologic context and a weight-of-evidence approach. Most CP biomarkers do not have the potential to be adverse in isolation, regardless of magnitude of change. Rather, they quantify or describe the impact of effects, provide adjunct or supportive information regarding a process or pathogenesis, and provide translational biomarkers of effect. Most often, CP changes are part of a constellation of findings that collectively are adverse. Thus, most CP changes must be interpreted in conjunction with other study findings and require contextual and integrative interpretation. Exceptions include critical CP changes without correlates that indicate a health risk in the tested species. Overall, CP changes should not be interpreted in isolation and their adversity is best addressed with an integrated approach.

| INTRODUC TI ONAccurate, informative, and integrated reporting of toxicologic clinical pathology results has become a fundamental expectation in contemporary drug safety submission packages. The approach to clinical pathology reporting has historically been quite diverse due to the wide spectrum of individuals and organizations tasked with clinical pathology interpretations and generating reports, and the lack of specific regulatory guidance on reporting standards. The purpose of this manuscript is to present an overview of current clinical pathology reporting practices within the drug development industry, as well as to provide a framework that will help authors draft meaningful clinical pathology interpretive reports in support of nonclinical toxicology studies. The suggestions provided are neither intended to be prescriptive nor to constrain report authors to follow a rigid, standardized structure. Reporting practices should be appropriately adjusted according to organizational standards, study design, and results of each study. By using these principles, the clinical pathology report can serve as an essential asset in support of nonclinical safety studies, and not become just a data dump of statistically significant differences or values that fall outside of historical control ranges. | COMP ONENTS OF A CLINIC AL PATHOLOGY REP ORTEffective communication of clinical pathology findings can be performed in a variety of ways, including (a) a stand-alone clinical pathology subreport, (b) an integrated anatomic and clinical pathology report, or (c) incorporation of clinical pathology results into the main study (toxicology) report. Because there is no formal regulatory guidance specifically addressing clinical pathology reporting Abstract Clinical pathology reporting practices are diverse among individuals and organizations involved in nonclinical toxicology studies. Clear, informative, and consistent reporting of clinical pathology results increases their value and avoids misinterpretation, resulting in decreased drug development costs. In recent years, certain common practices in clinical pathology reporting have been embraced by industry leaders and more consistently utilized across the pharmaceutical industry. The purpose of this manuscript is to review current clinical pathology reporting practices and to provide nonbinding suggestions to improve consistency, quality, and value of clinical pathology reports generated in support of nonclinical toxicology studies. K E Y W O R D S clinical pathology, interpretation, nonclinical studies, reporting, toxicology

Cytological bone marrow evaluation is utilized in nonclinical toxicology studies to characterize hematopoietic effects when the combined interpretation of histologic and complete blood count data does not yield sufficient information. Results from cytological bone marrow examination should be interpreted in the context of variability observed in concurrent control animals with consideration of cytologist experience and historical/published data. Cytological bone marrow differential counts and cellular morphologic findings from 130 (66 male, 64 female) healthy control cynomolgus monkeys from nonclinical toxicology studies were retrospectively analyzed. Myeloid to erythroid (M:E) ratios and the percentage of total cells for each cell type were determined from differential cell count data. M:E ratios ranged from 0.6:1 to 2.3:1. Percentages of total granulocytic cells, total erythroid cells, and lymphocytes ranged from 26.6% to 60.6%, 25.7% to 52.2%, and 5.5% to 40.4%, respectively. Monocytes, plasma cells, mast cells, and mitotic figures were typically <1% of total cells. Notable morphologic findings included occasional giant neutrophilic metamyelocytes and band neutrophils, ring-shaped band neutrophil nuclei, metarubricyte nuclear blebbing and binucleation, multiple or nonfused megakaryocyte nuclei, and emperipolesis. These results represent cytological bone marrow findings from healthy control cynomolgus monkeys utilized in nonclinical toxicology studies and provide insight into expected background variability.

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