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Slide 1-

The Role of Pathology in Drug Safety Evaluation John L. Vahle, D.V.M., Ph.D., Diplomate A.C.V.P. Research Advisor - Pathology, Toxicology Lilly Research Laboratories Division of Eli Lilly and Company
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Toxicologic Pathology Pathology as a Discipline Role of Pathology in Drug Safety Evaluation Training of Pathologists Pathologists Who are they ? What do they do ? What makes them think the way they do ?
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The Discipline Of Pathology Toxicologic Pathology Clinical Morphologic Definition: The science of the structural and functional consequences of injurious stimuli
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The Discipline Of Pathology Major Disciplines Within Pathology Clinical Pathology Hematology Clinical Chemistry Urinalysis Morphologic (Anatomic) Pathology Gross Pathology (Necropsy Observations) Histopathology (Microscopic Observations) Electron Microscopy (Ultrastructural observations)
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Toxicologic Pathology Pathology as a Discipline Role of Pathology in Drug Safety Evaluation Training of Pathologists Pathologists Who are they ? What do they do ? What makes them think the way they do ?
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Role of Toxicologic Pathology Pathology plays a critical role in safety assessment of foods, drugs, chemicals, and medical devices Many of the data points in repeat-dose toxicity studies originate in pathology Accurate description and interpretation of pathology data are crucial for safety assessment
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Repeat-dose Toxicity Endpoints Live Phase Observations Physical Examination Neurologic Examination Daily Clinical Signs Cardiovascular Physiology HR, ECG, BP Toxicokinetics – exposure to drug Hepatic Enzyme Induction Clinical Pathology CBC, Coag, Chem, UA Morphologic Pathology Gross and Histopathology 40-50 tissues
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From glass slides to human safety assessment A descriptive and interpretive science
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Goals of the Pathology Evaluation Recognize, tabulate and categorize alterations Allows correlations between test material exposure and biological effects Identify potential compound-related effects Fulfill regulatory expectations in the evaluation of safety of medicines
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Responsibility of the Pathologist Separate normal biological variation and spontaneous disease from compound-induced changes Affect of compound on spontaneous disease Responsible for reliable and detailed description of changes Clear interpretation of the data
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Morphologic Pathology in Drug Safety Necropsy Specimen Preparation Histopathology Evaluation Histopathology Raw Data
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Importance of Necropsy Timely and accurate dissection procedures Careful and consistent collection of organs and tissues allows: Accurate organ weights High quality histologic preparations Systematic description and recording of gross pathology observations
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Specimen Preparation Tissues promptly and appropriately fixed Typically by immersion in neutral-buffered formalin Trimmed at standard locations SOP, trimming guides Processed in a manner that reduces variability among groups Mix treatment groups in processing and staining Slides should be identified with study number, animal number, and slide number
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Histopathology Evaluation Basics Pathologist should assure that standard sections of all protocol tissues and organs are present on the slides to be examined Documentation of missing tissues or regions Recuts may be required to complete evaluation Tissues may be evaluated animal by animal or organ by organ
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Alteration Identification and Description All alterations should be recorded and graded Test-article changes are often subtle microscopic alterations Must compare treated and control animals Blinded evaluations typically not appropriate for initial survey Allows separation of test-article changes from normal anatomic variability
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Histopathology Raw Data The signed pathology report is considered raw data Histopathology Data Table (individual and summary) Histopathology Narrative (written interpretation) The final pathology report represents the consensus of the primary and peer review pathologists Slides, tissues, paraffin blocks, and slides are archived Draft tables, notes, and peer review results may be discarded
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Clinical Pathology In Drug Safety Distinct Scientific Subspecialty Requires professional personnel Technical Execution Well trained laboratory staff Quality Instrumentation Data Interpretation Statistical and individual animal data review Synthetic interpretation across study data Reviews of Regulatory Guidance Toxicologic Pathology Volume 20, 1992 Weingand et al, 20:539-543 Hall, 20:472-476
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Value of Clinical Pathology Data Can be sensitive markers of alterations Increased hepatic enzyme activity prior to morphologic changes Can be very specific to organ system Troponins and myocardial alteration Can assess functional impact of injury Impact of a bone marrow lesion on peripheral hematologic values Can be evaluated over the course of a study Primarily in dog and monkey studies
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Toxicologic Pathology Pathology as a Discipline Role of Pathology in Drug Safety Evaluation Training of Pathologists Pathologists Who are they ? What do they do ? What makes them think the way they do ?
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Toxicologic Pathology Training Background in comparative medicine Formal Pathology Training On-The-Job Training Large data sets Hazard identification Safety assessment
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What makes them think the way they do ? Majority have veterinary medical training Additional training, experience, and expertise in: Diagnostic pathology Laboratory animal pathology Research techniques Toxicology testing Good Laboratory Practices (GLP) Approach varies by geography
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US-based Training Veterinary Degree (DVM, VMD) 4 year professional program Veterinary Pathology Training Academia Veterinary Teaching Hospital Diagnostic Laboratory Research Institute
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US-based Training Residency Training – Professional Practice Evaluation of microscopic slides Differential diagnoses Diagnostic techniques Comparative pathology Research Training Wide range of research areas with training in: Basic Science Experimental Design Statistics Scientific Writing/Grants
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US-based Training - Outcomes Board Certification American College of Veterinary Pathologists General goal of residency Multiple Components General Pathology – Basic Science Veterinary Pathology – Species/Specialty Specific Diagnostic Sections Gross, Histopathology, Hematology, Clinical Chemistry, etc Extremely Rigorous Historically low pass rate Research Degree PhD MS Opportunities for Post-doctoral work
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EU-based Training Training Programs Varies from informal mentorship to systematic training Both academic institutions as well as in-house training in toxicology labs Qualifying Examinations European College of Veterinary Pathology Royal College of Pathologists
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Japan-based Training Training Programs Typically based in academia (veterinary schools) Qualifying Exams Japanese College of Veterinary Pathologists
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Transition to Safety Assessment Individual Animal Diagnosis Diagnostic Pathology What’s wrong with my dog ? Focused Research Question Experimental Pathology Did Experiment A have Effects A,B,C ? Screening for Toxic Effects Pharmaceutical Toxicologic Pathology Did compound X cause any effects ? If so, what do they mean to safety in humans ?
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On the Job Training Grounding in mechanics of evaluating studies Mentoring Peer Review Pathology Rounds Broad Exposure to Multiple Phase of Development Experiences as a toxicologist, project manager, etc
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Summary Pathologists provide a detailed description of compound-induced effects Ensure that important findings are understood Describes potential pathogenesis of important findings to facilitate understanding what has occurred in animals Work with toxicologist and regulators to ensure appropriate evaluation of toxicity and risk of a new drug Allows clinical investigators to understand potential adverse effects in humans