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Underestimated Input of a Central Lab During
the Clinical Trial Planning PhaseBusiness Review Webinars
October 18th, 2016
Tomasz AnyszekMD, PhD, EuSpLM
• Synevo Central Labs’ Directorsince 2009
• Synevo Poland’s General Director and Board Member since 2014
• Responsible for clinical trials operations of the whole network
• Previously worked for Covance managing Virtual Central Laboratory (VCL) initiative since 2000
• MD and PhD from Jagiellonian University Poland
Michał DyśkoMBA Degree
• Head of Business Development at Synevo Central Labs since 2008
• Responsible for sales and marketing operations of the whole network
• Previously worked for 2 European CROs• 11+ years of experience in clinical research• MBA Degree at University of Quebec at Montreal
and Warsaw School of Economics
Global CRO Market Share by Phase 2014
13%
7%
14%
35%
11%
12%8%
PreclinicalPhase IPhase IIPhase IIIPhase IVCentral LabsOthersTotal
Market Value:$27 billion
$ 3.24 billion
Central Lab Industry• $3.65 billion market (2015)• 12% annual growth rate• 100% outsourced• Global business• Industry dominated
by global players
Lab Data in Clinical Trials*
Efficacy Data
• e.g. Cholesterol level in Hyperlipidemia patients
• e.g. Plasma Glucose in Diabetes patients
Safety Data
• Hematology• Chemistry• Urinalysis
Special Data
• PK/PD data• Genomic data• Biomarkers
*60-80% of the data generated during the conduct of clinical trials are produced by laboratories
Lab Types in Clinical Trials
Central Lab
One central location
Local Lab
in close proximity to individual clinical
study sites
Virtual Central Lab
group of labs across world under the umbrella of one
company
Core Labs
Lab tests, ECG, imaging e.g.
cardiovascular core lab
Analytical Labs
non-traditional tests (biomarkers, PK,
genetic)
Traditional Testing Specialty Labs
Central Lab Role in Clinical Trials
Project ManagementLaboratory
TestingInvestigator
SupportSample
Management Logistics Data Mgmt and Reporting
• Routine and safety analysis
• Advanced diagnostics
• Method development and validation
• Analytical expertise
• Dedicated and locally based staff
• Real-time query resolution
• Trainings
• Multilingual help desk
• Lab manuals and instructions
• Study-specific kits building
• Packaging and labels
• Quality Control
• In-house frozen logistics support
• Kits inventory monitoring
• Planning, tracking and reporting
• Ambient, refrigerated, frozen and combo shipments
• Ready shipping documents
• Couriers management
• Network of own couriers
• Integrated single database
• Standardized reference ranges and units of measure
• Electronic Data Transfer
• 21CFR Part 11 –compliant reporting technology
Full Coordination and Accountability
Central Lab Costs
Admin; 5% Data Man-agement;
10%
Analysis; 25%
Sample Reception; 10%
Transport; 25%
Kit Production; 10%
Dbase; 5%
Profit; 10%
Growing Complexity• New areas (genetic, genomic)• New methodologies• Growing importance of biomarkers• Globalization and harmonization
Possible Challenge:Lack of understanding of laboratory part by protocol authors or/and study parties
CommunicationSponsor
CRO
Laboratory
Sponsor
Laboratory
„Unnecessary Bottleneck”
Poll Question # 1
At what stage of a clinical trial do you engage a central lab?• Study protocol development• Finalization of the protocol• Providers’ selection
Case 1: BNP or NT-proBNP• Multinational cardiologic project • Patients with heart insufficiency • 50 sites in 7 countries.• Parameter: BNP serum concentration• Preliminary laboratory budget: € 800 000
BNP Structure
BNP Synthesis & Secretion
Endopeptidaze
pre-Pro-BNP (134aa)
Pro-BNP (108aa)
Signal peptide (26aa)
BNPNT-proBNP
J. Mair, Clin Chem Lab Med; 39(7):571-588.
BNP vs. NT-proBNP
clearanceendopeptidase KidneysXhalf-life time20 minutes 60-120 minutes
*J Endocrinol Invest 2001 Jan; 24 (1):24-30.
BNP
NT-proBNP
active non-active
The outcome: NT-proBNP (!)• Multinational cardiologic project • Patients with circular insufficiency • About 50 sites in 7 countries.• Parameter: NT-proBNP serum
concentration• Preliminary laboratory budget: € 500 000
Case 2: Identification of Mutations
Request: • Determination of the gene defect in
hemophilia AChallenge: • There are several
different tests available on the market
Case 2: Available TestsTest Name Factor 8 deficiency
(Hemophilia A)IVS-1 inversion
Factor 8 deficiency(Hemophilia A)MLPA (women)
Factor 8 deficiency(Hemophilia A)Sequencing
Price analysis costs:95 € per sample
analysis costs:175 € per sample
analysis costs:2000 € per sample
Material/volume EDTA-blood/ 1 tube EDTA-blood/ 1 tube EDTA-blood/ 1 tube
Method PCR-analysis
MLPA Gene sequencingTAT 10 working days
10 working days
15 working days
Comments Analysis does not include IVS22 inversion of F8 gene, which accounts for approx. 40% of severe hemophilia A cases.F8 mutations can occur at diverse sites in a variety of types, such as structural variation (inversions of intron 22 or intron 1) and sequence variation (insertion, deletion, andsubstitution).
Analysis does not include IVS22 inversion of F8 gene, which accounts for approx. 40% of severe hemophilia A cases.F8 mutations can occur at diverse sites in a variety of types, such as structural variation (inversions of intron 22 or intron 1) and sequence variation (insertion, deletion, andsubstitution).
Case 3: Shipment Boxes• Do not force your ideas• Give lab a chance to propose a solution• Utilize lab expertise and experience • Do not afraid of customized solutions• Ask for validation
of transport boxes
Case 4: Very Tight Deadlines
• Laboratory needs time to set-up a study• Set-up activities includes:
• CTLMS/LIS set-up• Kits production and
distribution• Preparation of study
documentation• Validation of laboratory
methods
Case 4: Very Tight Deadlines
Laboratory requirements:• Study requirements
understood and agreed• Contract in place• Study set-up: 2-8 weeks
Client expectations:• To start set-up activities next day• To send kits in a week
Case 5: Changes after study set-up
• Each change and modification requested after study set-up requires additional work and in many case may be simply not possible
• Remember about this and be ready foradditional costs
Case 6: Volume of Blood
• Important factor from clinical and ethical point of view, especially in „special” populations(children, anemia)
• The subject very often overlooked byauthors of study protocols
• Risk of problems during study registration (ethical committee)
Case 7: Calculation of eGFRCalculated GFR is very important parameter in many studies, but quite often wrong formulas are in use:• Cockroft-Gault formula• MDRD formula• CKD-EPI formula• Schwartz formula
Case 7: Calculation of eGFRCockroft-Gault formula:GFR (ml/min) = (140-age) * (Wt in kg) * (0.85 if female) / (72 * serum creatinine)
• PAST!!!!!• Shouldn`t be used any more!!!!!
Case 7: Calculation of eGFR
MDRD formula (simplified):GFR [ml/min/1,73 m2] = A x B x 186,3 / serum creatinine [mg/dl]1,154 x age0,203
A = 1 for men and 0,742 for women; B = 1 (caucasian, white), B = 1,21 (negroid, black)
• Cut-off value: 60 ml/min/1,73 m2
Case 7: Calculation of eGFR
MDRD formula - special analytical requirements for method for creatinine determination:• Method should be calibrated against ID-MS (isotope
dilution mass spectrometry).• Allowable imprecision <8% and systematic error
(against ID-MS) <5%.
Case 7: Calculation of eGFRCKD-EPI:GFR [ml/min/1,73 m2] = 141 x max (Scr/ĸ)α x min (Scr/ĸ)-
1.209 x 0,933wiek x A x B
• Scr – min. and max. serum creatinine concentration [mg/dl]
• ĸ = 0,7 (women) or 0,9 (men)• α = -0,329 (women) or -0,411 (men)• A = 1,018 (women) or 1,0 (men)• B = 1,0 (Caucasian, white) or 1,159 (negroid, black)
Case 8: Weekends & Holidays• Problems with samples collection
on Fri-Sun and samples delivery on Sat-Sun
• Different Bank holidays in different countries
• Turn-around-time: given in days or in working days?
Case 9: Sites Locations• Sites location should be communicated to laboratory as
early as it is possible • Sites list (initial) should
be confirmed before the study budgetapproval
• Possible challenges:• Courier pick-up time• Additional Costs• Longer TAT
Case 10: PBMC Isolation• Topics to discuss:
• Collection tubes• Procedure for isolation• Sample stability:
duration of shipment• Controlled temperature
• Everything should be discussed and agreed before the study set-up
• „Dry run” as an important verification
BRUSSELSHQ
Questions?
Michał Dyśko, MBAHead of Business DevelopmentT: +48 602 443 552E: [email protected]
Tomasz Anyszek MD, PhD, EurClinChemSynevo Central Labs DirectorT: +48 609 917 552 770E: [email protected]