Confidential

10TH ANNUAL BIOMARKER CONFERENCE

Vincent Drouillon, PharmD., Clin.BioSr. Director, Translational BiomarkerSolutions and Hematology

Covance Central Laboratory ServicesIndianapolis and Greenfield, IN, USA

Biomarkers in Discovery and Drug Development:Choosing the right CRO partner

Confidential

Agenda

• Importance of Biomarkers in discovery and drug development

• Choosing the right CRO partner for biomarkers:• Pre-analytical considerations• Analytical and regulatory challenges• ‘Smart’ Biobanking• Project management and Scientific support

• From Biomarker to Companion Diagnostics: lessons learnt

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Importance of Biomarkers in Drug Development

ADDRESSING THE HIGH ATTRITION RATE

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Innovation in the Biopharmaceutical Pipeline – Jan 2013 – G. Long & J. Works

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Importance of Biomarkers in Drug Development

IMPROVING APPROVAL RATE

4 Approved drugs | 2013. Report. U.S Food and Drug Administration

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Importance of Biomarkers in Drug Development

• ‘Safer drug, in greater numbers, approved more quickly’1

• Use of biomarkers highly featured in FDA Critical Path Opportunities list

• The 5 ‘R’ approach2: the right Target, Patient, Tissue, Safety, Commercial potential = reduced failure rate

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1 The AAPS Journal, 2007 9 (1), Article 10, “Biomarker qualification pilot process at the FDA”, F. Goodsais et al.2 “Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework”, Nature Reviews Drug discovery, D. Cook and al., Vol.13, June 2014, p.419-431

DO IT SMARTER, FASTER AND CHEAPER WITH BIOMARKERS

Reduced attrition in development = reduced cost of development = more affordable healthcare

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Analytical and regulatorychallenges

The right validation level at the right stage

Pre-Analytical considerations

Avoiding the ‘pre-analytical’ biomarker

‘Smart’ bio-banking

Project Management and Scientific Support

Choosing the right CRO partner for Biomarkers

Maximizing sample utilization

Driving biomarker studies through the challenges

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In-Transit Temperature Monitoring Transportation time vs. established stability Onsite Shipping Support Monitor, Intercept, & Re-ice as needed Pre-configured Shipping Materials

TRANSPORTATION

1,250,000 Shipments/Year 95 + Countries 99% On-Time Delivery

Pre-analytical considerationsAVOIDING THE ‘PRE-ANALYTICAL BIOMARKER’

SAMPLE COLLECTION

Non invasive whenever possible

Minimum volume of blood(to balance with potential retest and sample storage)

Sample type definition (collection tube/device)

Validation driven decisions

Standardized biomarker specific collection and shipping instructions in investigator manual and

planned logistics to minimize variability and maximize data yield

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Pre-analytical considerationsAVOIDING THE ‘PRE-ANALYTICAL BIOMARKER’

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Analytical and Regulatory ChallengesTHE RIGHT LEVEL OF VALIDATION

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• Sample Type, Collection and Handling• Linearity/Analytical Measurement Range (AMR) • Precision (intra- and inter-assay)• Accuracy/Recovery • Sensitivity/Limits of Quantitation • Analytical Specificity (Interference) • Dilution verification • Verification/Definition of Reference Interval • Stability (short- and long-term) • Specimen Carryover • Period of Analyte Stability (length of run)

FeasibilityExploratoryAdvanced

Validation types:

How will I know my test work? FIT-FOR-PURPOSE VALIDATION

Pre-ClinicalClinical

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Analytical and Regulatory ChallengesTHE RIGHT LEVEL OF VALIDATION

Feas

ibilit

yEx

plor

ator

yA

dvan

ced

Plate 1Performance

verification/FamiliarizationCurve fit

Minimum required dilution

Plate 2Linearity/AMR

Sensitivity/LLOQ/ULOQAccuracy/Recovery

Plate 3Precision (intra)

Precision (inter-run #1)Dilution verification

Plate 4Precision (inter-run #2)

Length of run

Plate 5Precision (inter-run #3)Freeze/Thaw stability

Plate 6Analyte stability day X

Carry-overInterference study

Precision (continued)

Plate 7Analyte stability day Y

Reference rangesPrecision (continued)

Plate nAnalyte stability day nPrecision (continued)

• Feasibility validation: go/no-go decision…• Exploratory validation: candidate selection, proof of concept in pre-clinical setting...• Advanced validation: first in human – full CLIA validation as needed.

If in doubt, talk to regulatory agency (FDA,EMA…)

Fit-for-purpose validation approach at Covance TBS – Immuno-assays

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Analytical and Regulatory ChallengesTHE RIGHT LEVEL OF VALIDATION

Concept Lead ID

LaunchCandidateSelection

Quality principles

Target ID In-vitroScreening

EfficacyScreening

LeadOptimizationToxicology

DefinitiveToxicology

ClinicalDevelopment

Post-LaunchActivities

GCP CAP/CLIAGLP GMP

Critical choice for ability to submit dataand time/cost optimization

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• Choosing the right technologysensitivity, quantitative vs. qualitative…

• Planning for data combinabilityinitial verification: inter-instrument/lab correlationmonitoring: use of existing external survey, ‘split testing’, internal QC program…

• Testing days and Turn Around Timeinclusion criteria, dosing…

• Timelines for assay development and or validationregulatory environment, LDT vs. IVD test, need of disease state samples for validation…

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Analytical and Regulatory ChallengesOTHER CONSIDERATIONS

Cost and Readiness directly driven by all these factors

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Retrospective study Prospective study Bridging study

TESTING IS NOT THE LAST STEP WHAT MAKES SAMPLES VALUABLE

Lab testing and clinical information Appropriate consent (think ahead!)

Smart BiobankingMAXIMIZING SAMPLE UTILIZATION

Volume Location

KEEPING TRACK OF SAMPLES

Stability Thaws

Physical protection Temperature control

KEEP YOUR SAMPLES SAFE

Backup storage Limit sample movements

Leverage IT solutions to consolidate information

>10,000,000 samples in biorepository13

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Project Management and Scientific SupportDRIVING BIOMARKER STUDIES THROUGH THE CHALLENGES

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Request

Feasibility assessment

Covance/Client

discussion

Final proposal

Work executionTroubleshooting

as needed

Reporting

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Pan-Covance Services

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Discovery, Lead Optimization, Research Models

Toxicology and Safety Pharmacology

Bioanalytical and DMPK

Translational Biomarkers Solutions (TBS)

Clinical Pharmacology

Clinical Development

Market Access

CAP/CLIA Central Laboratories

Research Preclinical Phase l Phase ll Phase lll Phase lV

DEVELOPMENT COMMERCIALIZATIONDISCOVERY

IND NDA

Covance generates more drug development data for the regulatory evaluation of efficacy and safety than any other company in the world

FROM DISCOVERY TO COMMERCIALIZATION

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Covance Central Laboratory ServicesTRANSLATIONAL BIOMARKER SOLUTIONS (TBS)

Research environment(«Quality principles»)

providing Flexibility and Agility

Discovery DevelopmentTarget discovery Lead

discoveryLead

optimization Pre-clinical Phase I Phase II Phase III

Translational Biomarker Solutions

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Informatics

Molecule Characterization

Cell Based AnalysisPathology core lab and Immuno-assays

Biomarker Strategy and Consulting

Covance Central Laboratory ServicesTRANSLATIONAL BIOMARKER SOLUTIONS (TBS)

Expertise in key therapeutic areas

► Oncology► Immunomodulation► Biologics► Vaccines/Infectious diseases► Endocrine/Metabolic

Dedicated Project Management

Assay development, validation and sample testing

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Covance Central Laboratory ServicesCAP/CLIA LABORATORIES

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North AmericaIndianapolis

EuropeGeneva, Switzerland

JapanKawagoe City

ChinaShanghai

Asia/PacificSingapore

Key locations for timely and consistent processing of patient samples around the worldFull combinability of results between laboratories

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Covance CLS Laboratory Service Continuum>600 ASSAYS IN-HOUSE

Genomics ServicesDNA/RNA IsolationSequencingPCR

Safety TestingWide rangeAutomated testing

HematologyWide-ranging servicesSide-effect detectionAnemia evaluationCell counts

Special ChemistryInclusion testsLCMS: steroids

Flow Cytometry8-color servicesCell surface markersCytokines, Reticulocyte counts

Anatomic PathologySpecimen managementTissue processing, Slide & tube creationHistochemical stainingDigital Imaging, IHC & FISH

ImmunochemistryCancer-specific antigensHormone levelsOncoproteinsRIA/IA & ELISA

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From Biomarker to Companion Diagnostics: lessons learnt

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EmergingBiomarkers

ExploratoryBiomarkers

ValidatedBiomarker

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• Rx / CDx co-development involves 2 trialsdevelopment is always behind schedule

• CDx manufacturer distinct from Rx clientparties have different goals!

• Strong Project Management is Essential Greater oversight of projects: define expectations and deliverables

Clearer definition of roles and responsibilities: for Sponsor, Dx partner and CRO

Enhanced communication at multiple levels : strong engagement by all parties is essential

• Not all assays are created equal Assay must be very robust in order to be ‘plug and play’ Development assays require more validation not less

From Biomarker to Companion Diagnostics: lessons learnt

A good upstream and integrated biomarker strategy facilitates CDx development

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Conclusion

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• Biomarkers are essential to improve drug discovery and development (safer drugs, sooner on the market and at a lower cost)

• Choosing the right CRO partner for biomarkers goes beyond selecting a reagent kit and an instrument!

• A well thought out biomarker strategy facilitates potential integration in the development process as a companion diagnostics

Confidential

QUESTIONS?