Scalable Digital Pathology in a Large, Preclinical Organization

1. Scalable Digital Pathology in a Large, Preclinical Organization Luc Chouinard, DVM, DACVP Scientific Director, Pathology

2. OVERVIEW • Charles River Preclinical Services • Current use of Digital Pathology in CRO • Future applications

3. A leading in vivo biology company $1.34B in net sales (FY 08) Unique portfolio of products and services focused on the research and development continuum for new drugs A multinational company with ~8,700 employees worldwide ~70 facilities in 17 countries Charles River Snapshot Corporate Headquarters Wilmington, MA

4. CR Global Footprint Existing Pharma / Biotech Cluster Emerging Market A global presence with proximity to our clients’ sites 4

5. Charles River Preclinical Services

6. PRECLINCAL/DISCOVERY Sites – Overview • PCS • Montreal – full service, all species, some disease models • Shrewsbury – full service, all species, some disease models • Edinburgh – full service, all species, non-pharma services • Nevada – historically only primates (inc repro), now offering rodent and dog toxicology, safety pharmacology, lab sciences • Pennsylvania – reprotoxicity, phototoxicity, neurotoxicity • Ohio – general toxicology, carcinogenicity • China– all species (initially ≤ 3 mo), GLP and non-GLP • Sherbrooke – all species, mainly general toxicology • PAI –Complete pathology services • DIS • MIR – imaging, oncology/inflammation rodent models • Piedmont – oncology models • Ceribricon- CNS rodent models

7. More pathologists than any other company in the world Assessment of pathologic changes in: Drug discovery Toxicology Animal colony maintenance Charles River Pathology Services

8. Value of digital pathology services for sponsors • Allow sharing/consultation across sponsor and CRO pathologists • Be aware of potential adverse findings earlier • Better understanding of the toxicity profiles by making comparisons easier • Avoid inefficient sharing of partial images or lengthy discussion (via teleconference) to describe a finding • Reduce costs and time delays in pathologist travel and shipping of slides • Allow sharing with consultants

9. Value of digital pathology for CRO • Further enhances client relationships • Enhance consistency • Improve training • Improve standardization • Improve productivity • Cost saving

10. CRO Preclinical Pathology Challenges • Quest for faster reporting and effectiveness • Shorten turnaround time for consultations • Limiting travel for peer review on site • Avoid days or weeks for the transportation of glass slides • Potential issues with border/custom and international laws

11. PCS MTL experience • Installation of a high capacity scanner Q1 2008

12. PCS MTL number • 17 Pathologists • 1.5 M tissues processed/year • 35 000- 45 000 slides prepared/months • Average 6 peer review/week • 3 on site; 3 ship to sponsor

13. PCS MTL Digital Pathology Team • 3 administrators • Manage the Internal and Client accounts. • creating user and/or administrator accounts • assigning access levels • password administration

14. PCS MTL Digital Pathology Team • Manage scan requests and all steps towards generation of the virtual images for users • Contact material preparation group for slides access and ensure adequate slide condition prior to scanning

15. PCS MTL Digital Pathology Team • Contact the pathologists and clients with access info • Help desk/trouble shooting with clients • Responsible for deleting images/slides on servers as per guideline

16. PCS MTL Digital Pathology Workflow

17. Metada and Laboratory information system Local IT solution Interfacing to laboratory information systems SLIDE LOADER 1.0.1 • No Barcoded slides! • Metadata transfer from two sources Proventis (LIMS) and PLS form (histology lab database)

18. Slide loader 1.0.1

19. Metadata transfer - interdepartmental information –systems-applications

20. GUIDELINES • PROCESS FLOW FOR SCANS • REQUEST FOR SCANS • MATERIAL PREPARATION GROUP - SLIDE RETRIEVAL AND LOADING • MANUAL SCANS • AUTOMATIC SCANNING • TRACKING OF REQUESTS FOR SCANS • DIGITAL SLIDE CONFERENCING • DELETING IMAGES • TROUBLE SHOOTING NOTES

21. PCS MTL Data since installation

22. More than 4000 slides scanned 200 requests 85 % client related Slides scanned from 155 projects 95% reduction of internal photomicrography needs PCS MTL Data since installation

23. External Consultation Internal Training & Meeting QC Formal Complete Peer Review Full tissue complete GLP study evaluation YES YES YES NO NO Current use

24. PCS MTL experience Scanning protocols • Not routine for all sponsors or projects • Case by case needs for the majority • Scan selection of tissues, targets or unusual changes for discussion in the majority of the cases. • Generally limited to 10-30 slides/study. • Scan of all tissues in preterminal death in a few occasions

25. PCS MTL experience • Improved Pharma-CRO partnership Pre-study or pre-report meeting (TC, Web) Review\Discuss\Share Slides • Key findings • Previous studies • Potential targets • Glossary • Grading

26. Toxicity Study Dose Group Comparison

27. Toxicity Study Dose Group Comparison

28. Toxicity Study: Terminology and Grading

29. Challenges • Acceptance • GLP & Implementation & Validation

30. STP position paper Pathology Image Data

31. STP position paper Pathology Image Data • Pathology images (printed, electronic, or digital) used for data generation (e.g., to make a diagnosis or for morphometric analysis) are rawdata that must be authenticated and archived.

32. Important notes from the STP position paper During an informal pathology review, the opinions of any consulting pathologists are not binding on the study pathologist. The preamble to the GLP Regulations, as amended on September 4, 1987, and published in the Federal Register (Volume 52, No. 172, pages 33768-33782), states that: “. . . . pathologists interim notes, therefore, which are subject to frequent changes as the pathologist refines the diagnosis, are not raw data because they do not contribute to study reconstruction Accordingly, only the signed and dated final report of the pathologist comprises raw data respecting the histopathological evaluation of tissue specimens.”

33. STP position paper Pathology Image DataInformal Consultation Informal pathology consultation before the pathology report is completed is a common practice in toxicologic pathology. Informal discussions and any associated images are not pathology raw data

34. Future of Digital Path in CRO • GLP use • Enhance use of automated function and analysis Hematology Immunohistochemistry Morphometry Histology pattern recognition-CAPS

35. The future of Digital Pathology

36. Summary • The introduction of digital pathology in a large CRO had an immediate and significant impact despite current limitations and challenges Improved • Efficiencies • Partnership • Training • Overall Quality of Services

37. Summary The future is promising! Acceptance and new automated applications will modify the role of pathologists to further facilitate interpretation and improved translational toxicology

38. Thank you