1 CLINICAL TRIALS Digital Pathology in the Era of Global Clinical Trials: Improving Quality and Consistency Ron Luff, MD, MPH

2 CLINICAL TRIALS Global Reach USA UK Singapore Australia Belgium China Quest Diagnostics Clinical Trials Laboratories & Offices Affiliate Laboratories India

3 CLINICAL TRIALS Two facilities in Los Angeles (Lab and Project Mgmt), plus a lab in San Juan Capistrano, CA (Nichols Institute), a lab in Teterboro, NJ and an administrative facility in Collegeville, PA – >300 US employees – Service Areas include: o North America o Central America o South America o Australia o South East Asia Proprietary Facilities: US, UK, and India Two facilities near London (Heston – Lab; Hounslow – Proj. Mgmt), plus Project Mgmt in Wavre, Belgium – ~300 EU employees – Multiple language expertise – Services Areas include: o Europe o Middle East o Africa o India New 65,000 sq.ft. laboratory in Gurgaon, India (New Delhi); supporting local investigators / trials and global clinical trials – Service Areas include: o India o Pacific Region

4 CLINICAL TRIALS Core Competencies by Therapy

5 CLINICAL TRIALS Cellular Pathology, circa 1858-present Light microscopy “art-form” Variation of diagnoses among “experts” “Truth” often determined by majority rule in adjudication for clinical trials cases

6 CLINICAL TRIALS Digital Cellular Pathology, circa 1996-present QDC 146 GB SQL/Server Meta Data Database CLARiiON Quest Diagnostics’ reference laboratory placed 4 scanners in 2007 (Nichols Institute) Primary use −Remote viewing of reference IHC cases in a faster, yet equally accurate manner −Digital analysis when requested (eg, Ki67 quantitation) Digital Pathology WAN Chantilly, VA NS40 PSI San Juan Capistrano, CA NAS NS40 PSI 5tb CIFS Share 5 tb CIFS Share

7 CLINICAL TRIALS Digital Pathology for Clinical Trials, circa 1996-present Reduce variation of diagnoses and allow for “remote” prospective reads by central pathologist(s) Standardization among different labs

8 CLINICAL TRIALS Digital Pathology for Clinical Trials Additional Advantages Long-term storage of images –“Digital” slide –No risk of breakage and stain fade –Enables use of tissue section for other purposes (eg, DNA studies) Remote “anytime” access to digital slides –Enables trial sponsors to study slides Conferencing capabilities –Multiple people can review slides simultaneously

9 CLINICAL TRIALS Digital Pathology for Clinical Trials Additional Advantages Digitized slides can substitute for tissue/ cytology samples when global trial host country restricts exportation Digital analysis can be used for –Quantifying stains –Microvessel density assessment –Rare event detection –Protein quantitation within cellular compartments when used in conjunction with immunofluorescence

10 CLINICAL TRIALS Epidermal Growth Factor Receptor (EGFR) Part of a family of four related cell surface tyrosine kinase receptors Often mutated and upregulated in epithelial cancers (NSSC of lung, head and neck squamous carcinoma, colon adenocarcinoma) Overexpression predicts response to certain therapies (eg, gefitinib) EGFR status determined by FISH or immunohistochemistry (IHC) staining – until recently, subjective interpretation

11 CLINICAL TRIALS IHC Staining for EGFR Strongly Positive??Positive 20X 400X

12 CLINICAL TRIALS Digital Assessment Digital computerized assessment of membrane receptor –3+ Cells = 174 –2+ Cells = 153 –1+ Cells = 78 –0+ Cells = 36 –Total Cells = 441 Analysis provided by Trevor Johnson, Aperio.