1CLINICAL TRIALS

Digital Pathology in

the Era of Global Clinical

Trials:

Improving Quality and Consistency Ron Luff, MD, MPH

2CLINICAL TRIALS

Global Reach

USA

UK

Singapore

Australia

Belgium

China

Quest Diagnostics Clinical Trials Laboratories & Offices

Affiliate Laboratories

India

3CLINICAL 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 Americao Central Americao South Americao Australiao 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 Europeo Middle Easto Africao 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

4CLINICAL TRIALS

Core Competencies by Therapy

Experience (# Studies completed from 1996-2007)

633

506

427

407

392

390

336

286

214

206

108

335CNS

ONCOLOGY / HEMATOLOGY

CARDIOVASCULAR

NUTRITIONAL & METABOLIC

IMMUNO / INFECTIOUSDISEASEPULMONARY

PSYCHIATRIC

GENITOURINARY-OB/GYN

ARTHRITIS

GASTRIINTESTINAL

DERMATOLOGICAL

OTHER

5CLINICAL 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

6CLINICAL TRIALS

Digital Cellular Pathology, circa 1996-present

QDC

146 GBSQL/ServerMeta DataDatabase

CLARiiON

• Quest Diagnostics’ reference laboratory placed 4 scanners in 2007 (Nichols Institute)

• Primary use

−Remote viewing ofreference IHC cases ina faster, yet equallyaccurate manner

−Digital analysis whenrequested (eg, Ki67quantitation)

Digital Pathology

WAN

Chantilly, VA

NS40 PSI

San JuanCapistrano, CA

NAS NAS

NS40 PSI

5tb CIFSShare

5 tb CIFS Share

7CLINICAL 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

8CLINICAL TRIALS

Digital Pathology for Clinical TrialsAdditional 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

9CLINICAL TRIALS

Digital Pathology for Clinical TrialsAdditional 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

10CLINICAL 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

11CLINICAL TRIALS

IHC Staining for EGFR

Strongly Positive ??Positive

20X

400X

12CLINICAL 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.