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American Society for Veterinary Clinical Pathology
2424 American Lane
Madison, WI 53704

Telephone: +1-608-443-2479
Fax: +1-608-443-2474
email: info@asvcp.org

ASVCP, Regulatory Affairs Committee

Guidelines for Externships in Industrial Clinical Pathology

 

Goals:

  1. To provide the clinical pathology resident with experience in and exposure to laboratory animal clinical
    pathology as well as industrial clinical pathology.
  2. To partner organizations providing externships in industrial clinical pathology with academic institutions.

Purpose: The purpose of this document is to provide a list of general areas and specific issues in which the resident may gain introduction and experience during the externship process.  This guideline is provided for informational purposes to help guide the externship process and is not a mandatory list.

Expected results:  At the end of the industrial clinical pathology externship the clinical pathology resident should have become familiar with the clinical pathology of laboratory animals, should understand the approach to interpretation of clinical pathology data in the field of preclinical safety as it pertains to report writing, should understand the various roles of a clinical pathologist in industry, and should be able to relate their knowledge of general pathology to the drug development process.

 

General Information
Area Specific Issues
Timing and length of externship
  • 1-6 weeks (to be determined by hosting company)
  • Typically end of 2nd or 3rd year of residency, but first year residents may also be considered
Readings and references for laboratory animal clinical pathology and toxicology
  • Loeb and Quimby's The Clinical Chemistry of Laboratory Animals
  • Schalm's Veterinary Hematology: Introductory chapter and chapters on laboratory animal and non-human (NHP) hematology
  • The Laboratory Rat. chapter 5: Clinical Pathology of the Rat
  • Hall, Animal Models of Toxicology: Clinical Pathology of Laboratory Animals. (2007), chapter 12
  • Handbook of Toxicologic Pathology, Applied Clinical Pathology in Preclinical Toxicology Testing, chapter 6
  • Weingand, 1996 Harmonization of Animal Clinical Pathology Testing in Toxicity and Safety Studies, Tox Sci Vol 29/No 2.
  • Hall & Everds Principles and Methods of Toxicology (2008), 5th edition, chapter 26
  • Casserette and Doul's Toxicology
  • Stockham and Scott's Fundamentals of Veterinary Clinical Pathology: Chapter 1 Introductory Concepts (especially sections pertaining to quality of laboratory results, differences in methods and comparison of assays)
  • Veterinary Hematology and Clinical Chemistry, MA Thrall (ed.):  Chapter 1 (lab instruments/QC/Westgard rules)
  • Toxicologic Pathology: Introductory chapter 
  • Articles on laboratory animal bone marrow evaluation, such as WJ Reagan, et al., Tox Path vol 39/2011 and A Provencher-Bolliger, VCP vol 33/No.2/2004
  • Articles on liver toxicology such as: VL Boone, D. Meyers, et al VCP, vol 34/No. 3/2005 and EMEA 2005 Recommendations from the Reg. Affairs Cmt. On Identification and interpretation of Indicators of Hepatic Injury in Preclinical Studies.
  • One guidance paper on assay validation or Westgard, Basic Method Validation, 3rd edition
Regulatory guidances
  • FDA, 21 CFR Part 58, Good Laboratory Practice Regulations and Organization for Economic Co-operation and Development (OECD), Good Laboratory Practice, 1997
  • ICH S6 - Preclinical safety evaluation of biotechnology-derived pharmaceuticals
  • ICH S8 guidelines on immunotoxicology evaluation
Area of expertise
  • Recommended Objectives
Preclinical safety drug development
  • Write a preclinical safety report understanding the structure and purpose of the report - providing a document that accurately reflects the data and can be used by primary scientist and end users, such as management and regulatory agencies, for development of a compound into a medicine.
  • Additional activities, if time and availability permit:
  • Stages of drug development USA; discovery, pre-IND, IND, Phase 1, Phase 2, Phase 3, NDA, Post-marketing
  • Gain understanding of in-life, preclinical, toxicology assessments for small molecules; acute, subchronic, chronic, reproductive, and carcinogenicity studies including parameters monitored
  • Gain understanding of in-life assessments for large molecules
  • One-on-one meetings with members of preclinical drug safety development team such as study director, compound director, toxicology technicians, animal care technician, anatomic pathologist, animal care veterinarian, individuals from toxico- and pharmacokinetics, immunotoxicologist, biomarker developer, clinical pathology manager, necropsy personnel, etc.
  • Attend study pre-initiation meetings
  • Attend clinical pathology/anatomical pathology group meetings discussing findings on a particular toxicology study
Laboratory Management
Methods of sample collection in laboratory animals
  • Animal use and care guidelines: Guide for the Care and Use of Laboratory Animals: Eighth Edition, 2011
  • Sites of collection
  • Sample sizes and sampling times
  • Effect of site
Clinical Pathology Laboratory
  • Read main SOPs for sample collection, acquisition, storage and evaluation
  • Observe technical staff process samples and run laboratory
  • Look over instrument validation studies, set up and analysis
  • Study parameter documentation
Working in a regulatory GLP/OECD laboratory environment (general)
  • SOP's
  • Validations (method, computer system)
  • Method validations and QC using acceptance criteria in light of total error, systematic and random error and Westgard Rules
  • Documentation
  • Archiving (incl. slides etc.)
QC and QA in a regulated environment
  • Understanding the role of QA in a preclinical safety environment

Additional activities, if time and availability permit:

  • Understand how to properly document data
  • Understand the role of QA in report writing
Bone marrow smear evaluations
  • How to make smears
  • How to perform bone marrow smear evaluation
  • When to perform bone marrow smear evaluation
Blood smear evaluation in non-companion animals
  • Familiarize with RBC and WBC morphology
  • Hematology of laboratory animal  species
  • Common hemoparasites of laboratory animal species
Data Interpretation
Group laboratory animal data interpretation vs companion animals
  • Regulatory requirements - types of studies required for IND, NDA, & drug approval
  • Standard clinical pathology parameters performed
  • Adverse vs. non adverse changes
  • Test-item related vs. non test-item related changes
  • Biological variation, reference ranges
  • Significance of changes (biological vs. statistical)
  • Large animal (NHP, dog) vs. small animal (rodent)
How to interpret data in light of a study protocol
  • Study design
  • Pre-treatment vs. post-treatment
  • Single animals (e.g. outliers) vs. groups
  • Different species (mice, rats, dogs, monkeys)
  • Vehicle effects
  • Concurrent control vs. historical controls
  • Subtle group changes
  • Atypical clinical pathology changes without veterinary disease correlate
  • Incidental changes, background changes/disease
  • Dose response
  • Reversibility
  • Correlation with clinical signs, organ weights, histopathology, toxicokinetics etc.
  • New tests, biomarkers (risks and pitfalls in regulatory documents)
General pathology
  • Importance of pathways and mechanisms targeted in drug development, with examples
  • How does drug mechanism of action and/or pharmacology affect clinical pathology parameters 
Specialty Areas, if time and availability permit
Immunotoxicology
  • Regulatory guidance
  • Immunostimulation vs. immunosuppression
  • Immunology parameters captured with clinical signs, routine clinical and anatomic  pathology
  • Standard immunotoxicology testing
Anatomic Pathology
  • Regulatory requirements
  • The work of an anatomical pathologist in industry
  • Correlation between histopathology and clinical pathology
  • Necropsy techniques

 

 

CFR = Code of Federal Regulations
EMEA = European Medicines Agency, an EU regulatory agency for the evaluation of medicinal.
FDA = Food and Drug Administration
ICH = International Conference on Harmonization
IND = Investigational New Drug Application
NDA = New Drug Application
TK = toxicokinetics
PK = pharmacokinetics
SOP = standard operating procedures
QC = quality control
QA = quality assurance
NHP = nonhuman primate