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: michal.dysko@synevo.eu

Tomasz Anyszek MD, PhD, EurClinChemSynevo Central Labs DirectorT: +48 609 917 552 770E: Tomasz.anyszek@synevo.eu