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Recommendations for Visiting Extern Curriculum in Toxicologic Clinical PathologyPrior to arrival Provide housing and transportation recommendations Background check and ARMS (i.e. Animal Rights Screening) check through Human ResourcesSign company confidentiality agreement Look over curriculum and applicable reading list Week 1 ____________________________________________________________________________________Introduction Facility and Clinical Pathology lab tour Discussion of clinical pathologists role in pharmaceutical industry Academia and diagnostics vs industry/toxicologic clinical pathology CRO vs pharmaceutical companyInterpretation and reporting of clinical pathology data General structure, organization, and goals of a toxicologic clinical pathology report Recognizing biologic variation and procedure-related effects Direct vs indirect changes Significance of changes (biological and toxicological vs statistical significance) Discussion of adversity Training activities Interpret a small animal study and a large animal study (if time allows) Report to be in industry format, with review and discussion with a clinical pathologist Journal club discussion with focus on an article from the recommended reading list Attend integration meetings, scientific discussions as applicable Read recommended articles for Week 1Observation time in clinical pathology lab and necropsy (depending on interest) – focus on GLP documentation processes, QA/QC, how labs handle large volumes of samples, etc. Week 1 Reading list: Tomlinson L, et al. Best Practices for Veterinary Toxicologic Clinical Pathology. Vet Clin Path. 2013; 42(3): 252-269. Walter GL, Smith GS and Walker RM. Interpretation of Clinical Pathology Results in Non-clinical Toxicology Testing, Chapter 29 In: Haschek and Rousseaux’s Handbook of Toxicologic Pathology, 2013. Tripathi N, et al. Deciphering sources of variability in clinical pathology. Toxicol Pathol. 2017 (45)1: 90-93. Aulbach A, Provencher A and Tripathi N. Influence of study design variables on clinical pathology data. 2017. 45(2): 288-295. Ramaiah L, et al. Principles for assessing adversity in toxicologic clinical pathology. Toxicol Pathol. 2017; 45(2): 260-266.Schultze A et al. Veterinary clinical pathologists in the biopharmaceutical industry. Vet Clin Pathol 2008; 37(2): 146-158.Schultze A. Veterinary clinical pathologists have an impact on science and the biopharmaceutical industry. Vet Clin Pathol. 2011 40(2): 117-anization-specific style guidelines documentWeek 2Topic Discussions with Clinical Pathologists: Interpretation and reporting of clinical pathology data Study design effectsCorrelations with in-life, toxicokinetics, and anatomic pathology data Food consumption effectsStress effectsRoute of administration effects (e.g. infusion) Background changes/diseases (i.e. CPN in rats, menses in monkeys, Gottingen thrombocytopenia, etc.) Blood smear and bone marrow evaluations Discussion of differences in preclinical vs diagnostic environment When to perform bone marrow evaluation RBC and WBC morphology in lab animal speciesEffect of collection site Training Activities: Interpret a small animal study and a large animal study (if time allows) Report to be in industry or boards format, with review with a clinical pathologist Journal club discussion with focus on an article from the recommended reading list Attend integration meetings, scientific discussions, as applicable Discussion with anatomic pathologist(s) – their role and how they work together with clinical pathologists Review blood smears and bone marrows from laboratory species Reading list: Reagan WJ, et al. Best practices for evaluation of bone marrow in nonclinical toxicity studies. Vet Clin Path. 2011; 40: 119–134.Moriyama T, et al. Effects of reduced food intake on toxicity study parameters in rats. J Toxicol Sci. 2008; 33(5): 537-547. Zeng X, et. al. Effects of fasting on hematologic and clinical chemistry values in cynomolgus monkeys. J Med Primatol. 2011; 40: 21-26. Nancy E. Everds. Evaluation of Clinical Pathology Data: Correlating Changes with Other Study Data. Toxicol Pathol, January 2015; vol. 43, 1: pp. 90-97.Everds N, et al. Interpreting stress responses during routine toxicity studies: a review of the biology, impact and assessment. Tox Path. 2013; 41: 560-614. Hall RL and Everds NE. Factors affecting the interpretation of canine and nonhuman primate clinical pathology. Tox Path. 2003; 31(suppl): 6-10. Schalms Veterinary Hematology, Chapters on Laboratory animal species and nonhuman primate hematology or other species specific lab animal clinical pathology book chaptersWeek 3 and beyond:_____________________________________________________________________________________Additional topics and activities (depending on interest and time) Discussion with study directors and other study personnel on their role and interactions with clinical pathologists, study design considerations and regulatory requirements Shadowing with clinical vets to become familiar with laboratory animal medicine, dosing procedures, treatments, and other influences that may impact clinical pathology data Discussion with QA personnel and clinical pathology managers regarding GLP and QA in clinical pathology data generation and reporting Biomarker rounds topic – to be researched and presented by resident extern. Focus of the discussion should be on the utility of chosen biomarker(s), design of analytical and biologic validations, pitfalls/challenges unique to immunoassay biomarkers Additional topic discussionsStress in preclinical studies Assay validation Immunotoxicity Ancillary tests – platelet function testing, in vitro testing (hemolysis, CRA, etc.) Compound-specific toxicities and advanced studies Monoclonal antibodiesKinase inhibitorsOligonucleotides Vaccines Antibody-drug conjugatesMarrow stimulating agentsAdditional reading materials: Hall B, Principles of Clinical Pathology, Chapter 6 In: Toxicologic Pathology, Nonclinical Safety Assessment, 2013. Everds N, et al. Interpreting stress responses during routine toxicity studies: a review of the biology, impact and assessment. Tox Path. 2013; 41: 560-614. Boone L, et al. Selection and interpretation of clinical pathology indicators of hepatic injury in preclinical studies. Vet Clin Path. 2005; 34(3): 182-188. Lee J, et al. Fit-for-purpose method development and validation for successful biomarker measurement. Pharmaceutical Research. 2006; 23(2): 312-328.Harr K, Flatland B, Nabity M, and Freeman K. American Society for Veterinary Clinical Pathology (ASVCP). Guidelines for Allowable Total Error (Biochemistry). Vet Clin Pathol. 2013;42/4:424-436. Bente Flatland, Kathleen P. Freeman, Kristen R. Friedrichs, Linda M. Vap, Karen M. Getzy, Ellen W. Evans, Kendal E. Harr. ASVCP Guidelines: Principles of Quality Assurance and Standards for Veterinary Clinical Pathology Checklist, Control of General Analytical Factors in Veterinary LaboratoriesFindlay J, et al. Validation of immunoassays for bioanalysis: a pharmaceutical industry perspective. Journal of Pharmaceutical and Biomedical Analysis. 2000; 21(6): 1249-1273. Food and Drug Administration (FDA). Good Laboratory Practice for nonclinical laboratory studies, 21 CFR Part 58, 2012 Available at: Pathology: Nonclinical safety assessment. Chapter 1 (Overview of drug development) and Chapter 2 (Nonclinical safety evaluation of drugs). Guidance for Industry: S8 immunotoxicity studies for human pharmaceuticals.Lebrec H, Molinier B, Boverhof D, et al. The T-cell-dependent antibody response assay in nonclinical studies of pharmaceutical and chemicals: Study design, data analysis, interpretation. Reg Tox and Pharm 2014; 69: 7-21. Farmer JT and Dietert RR, Immunotoxicology Assessment in Drug Development, Chapter 14 In: A Comprehensive Guide to Toxicology in Preclinical Drug Development Amin K and Dannenfelser RM. In vitro hemolysis: guide for the pharmaceutical scientist. J Pharm Sci 2006; 95(6): 1173-1176. ................
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