Cristina Florescu Moraid

MD, MSc. EurClinChem

CLINIC LABORATORY

- ACTIV PARTICIPANT IN

CLINICAL TRIALS -

AGENDA

Purpose of the presentation � Clinical trial: definition, classification,

major players� Role of clinical laboratory� Rules to follow if participating in CT� Audits of clinical laboratory� Trends in clinical research industry� Synevo Central Lab experience� Conclusions

PURPOSE OF THE PRESENTATION

Why to talk about clinical trials?� Conducting CT represents an

average of 37% of the total cost to bring a new medicine to market

� R&D spending reached $140 billion by 2009

PURPOSE OF THE PRESENTATION

Laboratory vs R & D

� Laboratory testing represents a critical step in supporting the evaluation of a new product

� Laboratory industry generated in 2006 $1.8 billion dollars and reached $ 2.9 billion end of 2009

� Purpose of the presentation � Clinical trial: definition,

classification, major players� Role of clinical laboratory� Rules to follow if participating in CT� Audits of clinical laboratory� Trends in clinical research industry� Synevo Central Lab experience� Conclusions

AGENDA - cont’

CLINICAL TRIALS - definition

Clinical Trials are studies performed with human subjects to test new drugs or combinations, new approaches to surgery or radiotherapy or procedures to improve the diagnosis of disease and the quality of life of the patient

What is a clinical trial?(directive 2001/20/EC, art.2)

Any investigation in human subjects intended to

� discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s)

� and/or to identify any adverse reactions to an investigational product(s),

� and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.

What are the different types of clinical trials?

� Treatment trials : test experimental treatments, new combinations of drugs or new approaches to surgery or radiation therapy

� Prevention trials : look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning; e.g.: medicines, vaccines, vitamins, minerals

� Diagnostic trials : for finding better tests or procedures for diagnosis a particular disease or condition

� Screening trials : test the best way to detect certain diseases or health conditions

� Quality of life trials : explore ways to improve comfort and the quality of life for individuals with chronic illness

� Genetic studies, behavioral studies, epidemiology o r population based studies: as parts of cancer clinical trials

WHAT ARE THE PHASES OF DRUG DEVELOPMENT?

151413121110987654321

YEARS PHASE

NUMBER OF TESTED MOLECULES

1

2

2-5

5-10

10 - 20

3000 - 10000Basic researchSynthesis Testing Searching

Potential drug testing PRECLINICAL STUDIES

CLINICAL RESEARCHDrug testing

Drug registrationIntroduction to the market

Post registrationobservations

IV

III

II

I

•Early phase (Phases I and II)Safety and tolerance Clinical pharmacologyEfficacy endpointsSmall sample size

•Late phase (Phase III or pivotal study)Commercial scale and formulationLarge sample sizeGreater patient variability

•Post registration phase (IV)•Marketing support and line-extension

Phases of Clinical Development

� Phase I : Usually studies in health volunteers (“first in men”

(clinical pharmacology=pharmacokinetics & pharmacodynamic)

� Number of subjects: 12, 24 or 36

� Exceptions: studies in cancer research and other indications with chemotherapy(e.g. multiple sclerosis). In this cases pharmacokinetics will be investigated in patients

Phases of Clinical Development� Phase II : First studies in patients of interesting

indications(pilot studies” in efficacy, proof of concept, dose findings)

� Number of subjects: at least 8 up to 24 or hundreds

� Phase III : larger studies in patients of interesting indications (from a statistical point of view: ”confirmatory studies” in efficacy, tolerability)

� Purpose for registration, evidence for efficacy

� Number of subjects: from 50-60 up to thousands

Phases of Clinical Development

Phase IV / post marketing studies : same as for phase III; larger studies in patients of interesting indications, but after marketing authorization

Purpose: further evidence, other treatments schemes, marketing effects, drug’s risks

Number of subjects : according to statistical considerations, from

100 up to 10000 or more

The drug is on the market!

“Add on therapy”

WHO PERFORMS CLINICAL RESEARCH?

� Sponsors� Pharmaceutical Companies� Contract Research Organisation (CRO)

� Investigators� Site Management Organisation (SMO)� Physicians (investigators)

� LaboratorySponsor

CRO/SMO

InvestigatorLaboratory

Clinical trials - it’s all about data

Investigator Monitor

CentralLaboratory

Data Manager

Statistician

Clinician

RegulatoryAuthority

Subject

Diary

CRF

DCF

CRF DCFSample

LabResults

ClinicalData

NDA

� Purpose of the presentation � Clinical trial: definition, classification,

major players� Role of clinical laboratory� Rules to follow if participating in CT� Audits of clinical laboratory� Trends in clinical research industry� Synevo Central Lab Experience� Conclusions

AGENDA - cont’

Roles and ResponsibilitiesSPONSOR

Pharmaceutical Company� Drug development� Main sponsor contracts out different CROs

and/or InvestigatorsCRO

� Subcontractor to different pharmaceutical companies

� Responsible for clinical trials - Sponsor representative

INVESTIGATORSMO

� Clinical site coordinator - Investigator representative

Physician (investigator)� Subcontractor to SMO� Crucial part of clinical research� Direct contact with patient

INVESTIGATOR

INVESTIGATOR� Must be qualified (MDs)� Must have adequate resources (suitable subjects)� Must be compliant with the protocol� Is responsible for drug storage and drug

accountability� Should provide the subject ample time and

opportunity to inquire about details� The written consent should be signed before any

trial will start� Should promptly provide written reports to the

sponsor, IEC,etc,on any changes significantly affecting the conduct of the trial

� Must stay in close contact with laboratory and monitor

� Should report immediately all SAE s to the sponsor (SAE = death, life treating, teratogen effects, cancer, prolongation of hospitalization)

SPONSOR

� Is responsible for implementing and maintaining QA (quality assurance ) and QC (quality control) systems with written SOPs to ensure that trials are conducted and data are generated, recorded and reported in compliance with the protocol, GCP and applicable regulatory requirements

� A sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO (contract research organization)

� Should utilize qualified individuals (biostatisticians, pharmacologists, physicians) throughout all stages of the trial, to supervise the conduct of the trial, to verify the data, to prepare the trials records, etc

� Is responsible for selecting the investigators / institution/laboratory

� Ensure that the systems are designated to permit data changes in such a way that the data changes are documented and there is no deletion of entered data

MONITOR/CRO

� Should verify that the rights and well-being of the subjects are protected and the reported trial data are accurate, complete and verifiable from source documents

� Is responsible for verifying that the investigator has adequate qualifications and resources

� Verifying that the investigator follows the approved protocol and all approved amendment (s)

� Verifying the laboratory’s accreditation and GCP compliance

� Verifying that written informed consent was obtained before each subject’s participation in the trial

WHERE LAB CAN HELP?

� Sponsor level: study protocol design (e. g suitable blood volume, selecting the proper analyzing method and equipment, choosing proper test panels in relation to the study pathology, study specific data base, study specific report formats, method development according to study goal, etc)

� Monitor level: professional expertise for pre- and post-analytical phases of testing (e.g. sample preparation, sampling kits assembling, logistics tasks such as dry ice and courier providers, etc.)

� Investigator level: on site training for proper patient sampling, laboratory data interpretation referred to the study pathology, etc.

LABORATORY ROLE

Laboratory can play within a clinical study the role of:

� Local lab: only testing� Regional Lab: testing and

logistics� Central Lab: testing, logistics,

data and project management

� Purpose of the presentation � Clinical trial: definition, classification,

major players� Role of clinical laboratory� Rules to follow if participating in

CT� Audits of clinical laboratory� Trends in clinical research industry� Synevo Central Lab experience� Conclusions

AGENDA - cont’

Important definitions:

� GCP=good clinical practice� GLP=good laboratory practice� GLP doesn’t apply to laboratory testing

human samplesClinical means humans (GCP)Laboratory means others than humans

(GLP)� GLP doesn’t apply to clinical trials� GCLP=good clinical laboratory practice� GCLP applies exclusively to clinical trials

� Purpose of the presentation � Clinical trial: definition, classification,

major players� Role of clinical laboratory� Rules to follow if participating in CT� Audits of clinical laboratory� Trends in clinical research industry� Synevo Central Lab experience� Conclusions

AGENDA - cont’

Audit-a MUST for participation to CTICH-GCP (CPMP/ICH/135/95):

� Audit: ”A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were are recorded, analyzed and accurately reported according to the protocol, sponsor’s standard operating procedures (SOPs), Good Clinical Practice (GCP) and the applicable regulatory requirement (s).”

(Glossary, 1.6)

Audit-a MUST for participation to CT

ICH-GCP (CPMP/ICH/135/95):

� 5.19.1 Audits should be performed

“separate from routine monitoring or quality control functions”.

QC versus QA

� “Quality Control are the procedures in place toensure that the process is in control (the big Q)”

� “Quality Assurance is an audit function verifyingthat all QC procedures are effective (the little q).”

E.M.Sullivan, M.A. Gorko, R.C. Stellon & G. Chao (1997) Drug Information Journal

Planning of clinical studies

Identification of centres

General Management

Clinical Research

CRO

QA

Preparation of documents

Initiation of the study

Delivery of trial supplies

Data capture

Control of processes, dataand documents, SDV

Collecting materialand returned drugs

2nd Review of data (CRF)

Data Management, statistical evaluationand analysis

Final Report (E3)

M

o

n

i

t

o

r

QC

System Audit

General Management

Sponsor

CRO

QA

ExternalSystem Audits

Laboratory(Clin. or Bioanalyt.)

Data Management/Biostatistics

etc.

Guideline for Auditing Clinical LaboratoriesAudit covers:� Overall management of the facility� Quality management systems� The handling, analysis and result

reporting of samples reporting for samples processed

� Data management� Computer systems (compliance with

21CFR Part 11)� Archiving

9/24/2010 32

Auditor at work:

Clinical Laboratory Audit Checklist :1.Safety Resourcese.g. Is there a lab safety manual/ departamental safety manual? what is

the evacuation policy? UV light policy? emergency management policy?

2. Laboratory Housekeepinge.g. Are walls and ceilings clean and well maintained?

3. General Safety Awarenesse.g. Have all employees completed/reviewed the Laboratory Safety Evaluation Form within the last year? Have all employees who work with human blood/products been offered the hepatitis B vaccine?

4. Personal Protective Equipment (PPE)e.g. Do personnel decontaminate hands (i.e. handwashing) after removal of gloves? Is reusable clothing (i.e. lab coats) used for work with blood and blood products being collected in laundry bags that are either labelled or colour-codedas “biohazardous”?

5. Biological Safetye.g. Are surfaces on which work involving blood and blood products is performed routinely wiped down with an approved disinfectant at the end of the procedureor immediately following a spill?6. Fire Safetye.g. Are employees familiar with the location of fire extinguishers and pull alarms? Does the lab avoid placing electrical devices near water sources?

7. Chemical Safetye.g. Are the containers for all hazardous chemicals properly labelled with the chemical name, hazard type, and what to do if accidental contact occurs?

8. Quality Management Systeme.g. Are all relevant operations that are standardizable described in SOPs in writing?Describe, which operations are covered by SOPs. Is there evidence that all Individuals have access to the SOPs relevant to them and have they fully understandthe meaning? Will internal audits be performed on a regular basis?

If so, describe by whom and when

9. Specimen Handlinge.g. Are there procedures for specimen transport?Is there sufficient information to allow unique identification of:the patient?/ the specimen? Are details relating to the patient and specimen available?date and time of collection? type of specimen? investigations requested? date and time of receipt? clinical information?

10. Examination Procedures & Equipment

11. Staff Training

12. Reporting Results

Clinical Laboratory Audit Checklist :

� Purpose of the presentation � Clinical trial: definition, classification,

major players� Role of clinical laboratory� Rules to follow if participating in CT� Audits of clinical laboratory� Trends in clinical research

industry� Synevo Central Lab experience� Conclusions

AGENDA - cont’

Trends in clinical research industry

TALKING ABOUT THE PAST

� When a CT commenced and laboratory test data was returned, pharmaceutical companies would typically receive data with a 39% error rate

� Mislabeled test kits, incorrect tests, missing specimens caused data inaccuracies

DURING THE TIME…

� Analysis of CT data required months of work, with data having to be “cleaned” first before it could be analyzed

� Data was gathered from multiple local laboratories, that used different methodologies, reference ranges and SOPs

CENTRAL LABORATORY IDEA

� In order to deliver to study sponsors faster access to higher quality of data, faster receipt, analysis and a significantly reduced rate of error, the idea of CENTRAL LABORATORY has been conceived

CENTRAL LABORATORY IDEA-cont’

� Through the establishment of relationship with global logistics couriers, standardization in the production of sampling kits and the development of a single database, the CL industry has been able to deliver combinable data to CT sponsors

CENTRAL LABORATORY versus LOCAL LABS

� Investigators and sponsors expect lab results to be reported immediately after the central lab receives the samples

� Result reporting within 12-24h may be easy to achieve for routine testing methods

� For more complex and specialized methods, the frequency of running a specific assay in laboratory directly depends on the number of samples received

CENTRAL LABORATORY versus LOCAL LABS - cont’

� The high cost of instrumentation (up to $250,000) and reagents($1000 for a kit to test approximately 40 samples) in addition to qualified technicians, explain why laboratories need a minimum batch size to offer competitive lab fees to sponsors

CENTRAL LABORATORY versus LOCAL LABS - cont’

� A small laboratory processing 50 or 100 samples a day may only receive 5-10 samples for a specific immunology method

� This “imaginary” lab would only be able to run the immunology assay 2-3 times a month at a higher cost per unit

� A central lab with a capacity to process 5000 or more samples per day has the advantage of both offering competitive prices and reporting lab results with the shortest delays

What to use then?

HOW TO ANSWER TO THIS DILEMMA?

� Smaller laboratories may be good for local studies where testing portfolio is not too demanding, but they will not have the volume to cope with test panels that are becoming more complex

� Central laboratories following the strategies mentioned previously may succeed in supporting global studies if they have an established worldwide infrastructure and a solid quality system in place

WHAT IS THE TREND IN THE PRESENT?

� Nowadays, CT are globalized, places that may sound exotic such as Eastern Europe, Asia-Pacific or Latin America, offer distinct advantages for sponsors: large pools of treatment-naïve patients, faster and less competitive enrollment, lower costs per patient

� On the other hand, the increased logistics costs reffered to may be higher than the laboratory costs

� Also, a considerable number of samples are not able to reach the analytical facility under adequate conditions to be properly analyzed

� The patient recall for sample drawing may take up to one week, sometimes more, and represents a delay in the study schedule and negatively affect patient adherence

HOW TO SOLVE THE DILEMMA?

By using the Local Central Lab Model based on harmonization process

� Harmonized analytical platform� Harmonized reference ranges� Similar certification, accreditation and

external QC programs� Harmonized lab report formats� Harmonized database

� Purpose of the presentation � Clinical trial: definition, classification,

major players� Role of clinical laboratory� Rules to follow if participating in CT� Audits of clinical laboratory� Trends in clinical research industry� Synevo Central Lab experience� Conclusions

AGENDA - cont’

SYNEVO CENTRAL LAB(SCL)

� Leading provider of central laboratory services for clinical trials in Central and Eastern Europe (CEE).

� We are a part of MEDICOVER family (€200M revenues in 2009), the largest health service company in CEE.

� We are a shareholder in LabConnect, US-based central laboratory which operates across five continents.

24-Sep-10 47

OUR NUMBERS

� 14+ years of experience in clinical trials

� 30+ employees exclusively dedicated to clinical trials

� 50+ laboratories within the European network

� 200+ successfully completed projects

� 1500+ validated tests

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Coverage | Europe

24-Sep-10 49

Synevo Central Lab Operations

Strategic partners

Coverage | Global

24-Sep-10 50

EXPERIENCE SCL

Distribution acc. to phases

Central vs. local services

9/24/2010 General presentation 51

Worldwide CTs distribution4%3%2%2%1%

47%

15%14%

12%

Endocrino ORL Pediatrics

Psychiatry Neurology Rheumato

CV Diseases Pulmonary Dermato/Plastic surgery

Nephrology Musculoskeletal Immunology

Gastro Obstetrics Hemato

Onchology

Experience SCLTherapeutic areas

24-Sep-10 53

PRESENT SITUATION OF PROJECTS IN SCL Romania

31

8

53

Pipeline

Start-up phase

Ongoing

TOTAL 92 PROJECTS

CONCLUSIONS� None of existing treatments result in a cure of all

patients, nor are they without side effects, and doctors continue looking for better ways to treat t he disease

� Clinical laboratory plays a very important role in any clinical trial by offering reliable data for the pa tient’s diagnosis and the trial success

� Only by common effort of all involved partners in t he research field, better ways to treat disease will b e developed and the patients health status will be significantly improved

� Beside the other benefits reached by the participat ing into a clinical trial, none of us should ever forge t that everything starts and ends with the patient !