1. From Diagnosis to Conclusion
Jeffery A. Engelhardt, DVM, PhD, DACVP
Amgen Inc.
Thousand Oaks, CA

2. Pathologist’s narrative
Written pathology interpretation
Detailed description of findings
Clear interpretation and best judgment of importance of findings
Provide assurance that a thorough evaluation was conducted
Concise and explicit wording
Analysis is based on the treatment cohort rather than effects on individual animals
Need to consider individual effects in non-rodent species

3. Pathologist’s narrative
A clear well written pathology report is not always what is produced
Influenced by a variety of factors
Experience of the pathologist
Experience or perceptions of the sponsor

4. What does the Sponsor want from the narrative?
Sponsors will vary in expectations of the pathology reports from
Data tabulation of what occurred
Identification of compound-induced changes
Integrated assessment of effects in the test groups
Correlative presentation of effects in relation to exposure

5. What does the Reviewer need from the narrative?
Assessors need to know what was seen and what the pathologist thought of the findings
Clear indication of how data was assessed
Do not need
Obtuse or verbose presentation where significant findings are buried within the narrative
Data dump lacking interpretation
Broad sweeping assessments lacking rationale
Vague diagnoses

6. How are data sets integrated?
Varies among pathologists based upon training, experience, and conventions of employer
Generally need to evaluate data in terms of population pathology

7. How are data sets integrated?
Many ways to look at data sets
Statistical basis
Diagnosis basis
Incidence basis
Incidence and severity
Trends
Cut-off values for percentage increase in a parameter
Dose responsive or not
Spectrum of findings for a organ or system

8. Correlation of animal toxicity to man
Up to 71% correlation when similar organ systems are affected in both rodent and non-rodent species
63% correlation when only non-rodent affected
43% correlation when only rodent affected
Olson H, et al Reg Toxicol Pharmacol. 32:56-67.

9. Correlation of animal toxicity to man
Greatest correlation in predicting human adverse effects in
Hematological system
Gastrointestinal system
Cardiovascular system
Least predictive for effects on skin and hepatobiliary system
Olson H, et al Reg Toxicol Pharmacol. 32:56-67.

10. Special areas of interpretation
Systemic effects in animals in toxicology studies may have multi-factorial pathogenesis
Predominant pathway may be the most obvious or expedient, but others should be considered
More than one way to look at a particular finding

11. Special areas of interpretation
Stress
Multiple organs affected with correlative organ weight, morphologic, and clinical pathology effects
i.e., adrenal weights with hypertrophy, lymphocyte counts
Sometimes correlates are incomplete or inconclusive, so this may become a catch-all diagnosis
“All other effects on organ weights, etc., could be attributed to stress”
Need to present clear evidence to support this diagnosis

12. Special areas of interpretation
Dehydration
Multiple clinical pathology parameters support this diagnosis
Systemic effects on clinical pathology parameters
Present the correlative evidence in the narrative
Need to sort out primary and secondary effects on organs
What is really due to the test article?
Need to determine cause of dehydration
Often attributed to mechanical defect in watering system

13. Special areas of interpretation
Body weight loss
What is the cause
Decreased food consumption
Decreased body weight gain
EFU
Effects on organ weights and anatomic pathology
“Pattern of organ weight effects most consistent with effects on body weight”
Loss of body weight can lead to sweeping statements
Need to look closely for correlates in affected animals

14. Issues open to multiple interpretations
Evaluation of data sets is always influenced by training and experience
“I’ve seen this before” syndrome
Transferability of findings across species is not always correct or appropriate
Influence of internal review
Stand-alone pathology report
Combined toxicology report

15. Cause of death
The pathologist is responsible for identification of the cause of death as part of the interpretation of compound-induced effects
If cause of death is not apparent, this should be recorded as undetermined
Causes of death may include neoplasms, cardiomyopathy, chronic renal disease, trauma, or infectious diseases
G. Long Toxicol. Pathol. 32: , 2004

16. Cause of death
Cause of death for each animal should be determined qualitatively and utilize professional judgment
An interpretive diagnosis
Determination of cause of death is not always clear
Proximate cause may be difficult to identify
Diagnosis should be the overall process leading to the proximate cause
Contributory changes in organs may be integrated
G. Long Toxicol. Pathol. 32: , 2004

17. Pathologist’s narrative – What should be
In-depth discussion with perspective to support safety assessment
Statistical versus biological importance
Clear explanation of cause of death
Was mortality due to test compound?
Perspective on similar lesions induced by other compounds, a common mechanism of action, or spontaneous disease
At least list critical references
Historical data

18. Pathologist’s narrative – What should be
Correlation to other changes in the animals
Clinical observations
Aid in identifying target organs and potential mechanisms of action/toxicity
Body and organ weights
Primary and secondary effects on tissues
Hematology, clinical chemistry, and urinalysis data
Potential markers to monitor in patients
Metabolism and toxicokinetic data
Margins of exposure

19. Pathologist’s narrative – What should be
Large doses are used to assure measurable effects will occur in small populations of animals
Highest dose should cause overt toxicity
Lowest dose should not cause any toxic effects (NOEL)
NOAEL
Clear indication of criteria used to determine “adverse”
Perspective needs to be discussed by the pathologist
Work with the Study Director to provide a balanced integration and interpretation of the overall study

20. Pathology peer review Quality control mechanism
Ensure accuracy and completeness in recording histopathological findings
Control observational bias by the histopathologist
Standardize terminology and diagnostic criteria
Confirm target organs
Confirm NOEL and NOAEL

21. Pathology peer review
A second evaluation of a subset of animals and tissues
All tissues from 10% or minimum of 3/sex in high dose and control groups
Target tissues and equivocal alterations
Verification of cause of death
Ensures accuracy and consistency of terminology and severity grades for compound-related findings
Necessary to determine NOEL and NOAEL
Reviews the validity of the interpretation

22. Pathology peer review Differences of opinion Consensus Non-substantive
Literature, consultation, pathology working group
Non-substantive
Minor differences in terminology or grading that have no bearing on the overall interpretation of a study
Substantive
Identification of important new pathologic changes or differences of a least two severity grades

23. Pathology peer review
Document peer review with a signed Peer Review Certificate
Study Identification
Purpose and process of the review
Results of the review
How any differences in opinion were resolved
Worksheets and all other records made during review are not retained

24. Summary
Pathology data are qualitative, subjective, and descriptive rather than quantitative and objective
Causes interpretation differences and misunderstanding by regulatory assessors and sponsor toxicologists
Pathologists need to provide a detailed description of compound-induced effects and ensure that important findings are understood
Use standard and meaningful terminology to aid understanding by non-pathologist

25. Summary - The pathologist’s narrative
Describes potential pathogenesis of important findings for the regulatory assessor to understand what has occurred in animals
Facilitates appropriate evaluation of toxicity and risk assessment of a new drug
Allows clinical investigators to understand potential adverse effects in humans

26. Conclusion
The pathology evaluation should ensure that compound-induced alterations are presented
Clearly
Consistently
Accurately
Understandably
Importance of the findings for safety is explicitly identified for inclusion in the various regulatory documents

27. Questions

28. Panel Discussion
Toxicologic Pathology: From Diagnosis to Interpretive Narrative
What Pathologists Supply Versus What Reviewers Need