Biomarkers in Discovery and Drug Development: Choosing the right CRO partner
Transcript of Biomarkers in Discovery and Drug Development: Choosing the right CRO partner
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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
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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
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QUESTIONS?