Clinical trials are growing in complexity, particularly with regards to laboratories. There is a tendency to include unnecessary protocols and inappropriate laboratory procedures in studies that can lead to complicated study sample logistics and large courier costs as a result. Early engagement of a central lab during a clinical trial planning phase can save a lot of money and time for the study sponsor as well as a lot of unnecessary stress to the project management and investigator teams. We would like to share with you few real life cases that we have experienced in the last couple of years. We will present the consequences of the protocol's initial assumptions, our proposed solutions and the achieved results. In such a competitive market as Pharmaceuticals, drug developers cannot afford to waste money and must utilize expertise and experience of all clinical trials parties, especially central laboratories, at the earliest possible stage of a clinical trial.

1. Underestimated Input
of a Central Lab During
the Clinical Trial Planning Phase
Business Review Webinars
October 18th, 2016

2. Tomasz Anyszek
MD, PhD, EuSpLM
• Synevo Central Labs’ Director
since 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

3. Michał Dyśko
MBA 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

4. Global CRO Market Share by Phase 2014
13%
7%
14%
35%
11%
12%
8%
Preclinical
Phase I
Phase II
Phase III
Phase IV
Central Labs
Others
Total
Market
Value:
$27 billion
$ 3.24 billion

5. Central Lab Industry
• $3.65 billion market (2015)
• 12% annual growth rate
• 100% outsourced
• Global business
• Industry dominated
by global players

6. 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

7. 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

8. Central Lab Role in Clinical Trials
Project Management
Laboratory
Testing
Investigator
Support
Sample
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

9. Central Lab Costs
Admin, 5% Data
Management,
10%
Analysis,
25%
Sample
Reception,
10%
Transport,
25%
Kit
Production,
10%
Dbase, 5% Profit,
10%

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

11. Communication
Sponsor
CRO
Laboratory
Sponsor
Laboratory
„Unnecessary Bottleneck”

12. 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

13. 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

14. BNP Structure

15. 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.

16. BNP vs. NT-proBNP
clearanceendopeptidase Kidneys
X
half-life time20 minutes 60-120 minutes
*J Endocrinol Invest 2001 Jan; 24 (1):24-30.
BNP
NT-proBNP
active non-active

17. 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

18. Case 2: Identification of Mutations
Request:
• Determination of the gene defect in
hemophilia A
Challenge:
• There are several
different tests
available
on the market

19. Case 2: Available Tests
Test 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 sequencing
TAT 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,
and
substitution).
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, and
substitution).

20. 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

21. 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

22. 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

23. 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 for
additional costs

24. 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 by
authors of study
protocols
• Risk of problems
during study
registration
(ethical committee)

25. Case 7: Calculation of eGFR
Calculated 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

26. Case 7: Calculation of eGFR
Cockroft-Gault formula:
GFR (ml/min) = (140-age) * (Wt in kg) *
(0.85 if female) / (72 * serum creatinine)
• PAST!!!!!
• Shouldn`t be used any more!!!!!

27. 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

28. 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%.

29. Case 7: Calculation of eGFR
CKD-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)

30. 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?

31. 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 budget
approval
• Possible challenges:
• Courier pick-up time
• Additional Costs
• Longer TAT

32. 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

33. BRUSSELS
HQ
Questions?
Michał Dyśko, MBA
Head of Business Development
T: +48 602 443 552
E: michal.dysko@synevo.eu
Tomasz Anyszek MD, PhD, EurClinChem
Synevo Central Labs Director
T: +48 609 917 552 770
E: Tomasz.anyszek@synevo.eu