ECRIN - EURORDIS

ECRIN EUROPEAN CLINICAL RESEARCH

INFRASTRUCTURES NETWORK

Christian GluudCopenhagen Trial Unit

Centre for Clinical Intervention ResearchCopenhagen University Hospital

Denmark

ECRIN ECRIN EUROPEAN CLINICAL RESEARCH EUROPEAN CLINICAL RESEARCH

INFRASTRUCTURES NETWORKINFRASTRUCTURES NETWORK

Christian Christian GluudGluudCopenhagen Trial UnitCopenhagen Trial Unit

Centre for Clinical Intervention ResearchCentre for Clinical Intervention ResearchCopenhagen University HospitalCopenhagen University Hospital

DenmarkDenmark

What is ECRIN?

• Network of national networks

• Infrastructure to facilitate more research

•• Infrastructure to facilitate better researchInfrastructure to facilitate better research

What is ECRIN?




500 million500 million

8000 diseases8000 diseases

27 cultures27 cultures

29/04/200729/04/2007 www.ecrin.orgwww.ecrin.org 11

FranceInserm

SpainSCReN

SwedenSweCRIN

GermanyKKS

DenmarkDCRIN

ItalyIRFMN & CIRM

HungaryHECRIN

UKUKCRN

Ireland ICRIN

EFGCP

National networks of Clinical Research Centres / Clinical Trial Units

AustriaATCRIN

SwitzerlandSCRN

EORTC

FinlandFinnCRIN

ECRIN will provideintegrated, ‘one-stop shop’ services

• to investigators and

• to sponsors

- industry

- funders

- patient organisations

in multinational clinical trials

ECRIN will provide

- ethics and regulatory affairs approval- patient recruitment and investigation- data management - good manufacturing practice (GMP)

of biotherapy products- quality assurance- monitoring and - adverse event reporting

ECRIN will provide

- harmonisation of EU Directive- transparency in clinical research - registration of trial protocols before

inclusion of participants (WHO)- registration of anonymised

clinical trial data (EU TRIAL BANK)- increased information on clinical

research

What is ECRIN?




The hierarchy of evidence

Ia Systematic review of high-quality randomised clinical trials

Ib Single randomised clinical trial II Cohort studyIII Case-control studyIV Consensus reports, opinion of

‘experts’, narrative overviews,physiological studies

Dangers in non-randomised studies• Biological mechanisms

- Limited time of diseases- Cyclical progression of diseases- When do we see patients?

• Psychological mechanism- The Rosenthal effect, we see what we want

to see (BIAS)!- The Barnum effect, we believe what we want

to believe (astrology)!

• Confounding by indication

James Lind 1747

International Clinical TrialsInternational Clinical Trials’’ Day since 2005Day since 2005

Jules Gavaret 1840

Number of publications oncontrolled clinical trials per five-

year interval 1946-2006

0

2 0 0 0 0

4 0 0 0 0

6 0 0 0 0

8 0 0 0 0

10 0 0 0 0

12 0 0 0 0

14 0 0 0 0

19 4 6 19 5 1 19 5 6 19 6 1 19 6 6 19 7 1 19 7 6 19 8 1 19 8 6 19 9 1 19 9 6 2 0 0 1 2 0 0 6

Number of publications on clinical trials per country from 1946-2006

Number of publications onclinical trials

per million inhabitants per country

What is ECRIN?




Important aspects ofrandomised clinical

trials• Random errors• Systematic errors (bias)

Random errors in small trials• False positive results

(type I error)

• False negative results

(type II error)

Favor s Tr eatment Favor s Control

Study Year Pts 1 Flectcher

Odds Ratio 95% CI

Intrav enous Streptokinase Therapy for Acute Myocardial Infarction

0.5 1 2

P < 0.00 001Favor s Tr eatment Favor s Control

0.01 1 1000.1Odds Ratio 95% CI

Fixed Ef fects M odel (M ant el-Haenszel)

10

2 Dewar 3 European 1 4 European 2 5 Hei ki nhei mo 6 Ital i an 7 Au stral i an 8 Franfurt 9 NHLBI SMI T10 F rank11 Va le ri e12 Kl ei n13 UK -Col l ab14 Austrai n1 5 A ustral i an 216 Las ie rra17 N Ger Col l ab18 W itch itz19 European 320 I SAM21 GISS I-122 Olson23 Barof fi o24 Schrei ber25 Crib ier26 Sai nso us27 Durand2 8 Wh ite29 Bassand3 0 Vlay31 K ennedy3 2 ISI S-2

2365

232962

33 Wi senberg

OV ERALL 36974

1388170922262432253926472738276133564084431443384821487951946935

18647186991875818796188401893819002192211932819353197213690836974

Pts1959 231963 421969 1671971 7301971 4261971 3211973 5171973 206

1974 107 1975 1081975 911976 231976 5951977 7281977 2301977 241977 4831977 581979 315 1986 17411986 117121986 52

1986 59 1986 381986 44

1986 981987 64 1987 219 1987 1071988 251988 3681988 17187

1988 66

Systematic errors (bias) inrandomised trials

Methodological quality depends on:

Confidence that the design, conduct, and report of a trial

restrict bias in the intervention comparison

Components that must be adequate in randomised trials to

reduce bias

• Generation of the allocation sequence• Allocation concealment• Double blinding• Intention-to-treat analysis

Control of selection biasAllocation concealment

• AdequateCentral independent unit, sealed envelopes

• Inadequate Not described or open table of random numbers

Allocation concealment

Large RCTs

Small - Adequate

Small - Inadequate

ROR (95% CI)

1.00 (referent)

1.01 (0.48 - 2.11)

0.49 (0.27 - 0.86)*

*p=0.014

ConclusionsConclusions

•• Much has been achieved, butMuch has been achieved, but

-- too few trialstoo few trials

-- too small trialstoo small trials

-- too inadequate methodologiestoo inadequate methodologies

•• There is much more to achieveThere is much more to achieve

ConclusionsConclusions

•• ECRIN is ready to serve ECRIN is ready to serve EURORDIS and other patient EURORDIS and other patient

groups with rare and prevalent groups with rare and prevalent diseases regarding prevention, diseases regarding prevention,

diagnosis, and treatmentdiagnosis, and treatment

•• ECRIN salutes ECRIN salutes EURORDISEURORDIS’’ss

10 years!10 years!

Thank you !

What are the consequences of inadequate methodological quality?Methodological quality and intervention effect in

• 190 randomised clinical trials from

• 14 meta-analyses each including at least one large RCT(> 1,000 participants)

(Kjaergard et al, Ann Intern Med, 2001)

Methodological quality and intervention effect

• Large RCTs (n=23) Median number of participants = 1,741

(IQ: 1,290 - 4,396)

• Small RCTs (n=167)Median number of participants = 165

(IQ: 87 - 316)

Topic areas and outcomes

• Cardiology• Gynaecology• Psychiatry• Obstetrics• Smoking• Surgery

• Mortality• Endocervical cells• Treatment tolerance• Caesarean section• Abstinence• Deep venous thrombosis

Control of selection biasGeneration of the allocation sequence• Adequate

Computer system, table of random numbers, or similar

• Inadequate Not described or quasi-randomised

(excluded)

Generation of the allocation sequence

Large RCTs

Small - Adequate

Small - Inadequate

ROR (95% CI)

1.00 (referent)

0.90 (0.47 - 1.76)

0.46 (0.25 - 0.83)*

*p=0.011

Proportion of randomised trials in GASTRENTEROLOGY

with adequate generation of allocation sequence (Kjærgard et al. 2002)

Control of selection biasAllocation concealment

• AdequateCentral independent unit, sealed envelopes

• Inadequate Not described or open table of random numbers

Allocation concealment

Large RCTs

Small - Adequate

Small - Inadequate

ROR (95% CI)

1.00 (referent)

1.01 (0.48 - 2.11)

0.49 (0.27 - 0.86)*

*p=0.014


with adequate allocation concealment (Kjærgard et al. 2002)

Control of detection bias(reporting bias and observer bias)

Double blinding

• AdequateIdentical placebo or comparator

• Inadequate Not described or not blinded

Double blinding

Large RCTs

Small - Adequate

Small - No/inadequate

ROR (95% CI)

1.00 (referent)

0.84 (0.43 - 1.66)

0.52 (0.28 - 0.96)*

*p=0.01


with adequate double blinding (Kjærgard et al. 2002)

ConclusionsMethodological quality of ‘small’

RCTs affects the estimatedintervention effect

– On average, high-quality RCTsprovide reliable estimates

– On average, low-quality RCTsexaggerate the intervention effect with20%

Conclusions• RCTs should be done with

adequate sample size

• RCTs should be done with adequate methodological quality

Conclusions

• The sample size in most trials is insufficient

• No apparent association between the prevalence of the disease or the expected number of events and the average sample size

• The majority of trials in gastroenterology have inadequate methodological quality regarding- generation of the allocation sequence- allocation concealment- double blinding

• The methodological quality varies significantly within different disease areas

Conclusions

The CochraneCollaboration

An international network of professionals,preparing, maintaining, and disseminating systematic reviews of the effects of health

care

Archie Cochrane (1979)”It is surely a great criticism of our profession that we have not organised a critical summary, by speciality and subspecialty, adapted periodically, of all relevant randomised trials”

CC milestones, 2007

• 12 Cochrane Centres • 51 Collaborative Review Groups• 11 Method Groups• 13 Fields• 1 Network

COCHRANE CENTRES

Canadian

United Kingdom

Nordic

DutchItalian

Australasian

US Centre

Brazilian South African

Spanish

German

N=12Chinese

Cochrane Collaboration

Collaborative Review Groups

Fields

Consumer Network

Centres

Steering Group Methods

Working Groups

COLLABORATIVE REVIEW GROUPCOLLABORATIVE REVIEW GROUPReviewersReviewers

EditorialTeam

ReviewersReviewers

MODULE of edited protocols

and reviews

The Cochrane Database of Systematic Reviews in:The Cochrane Library

Translators

Hand-searchers Consumers

The Cochrane Library

www.cochrane.org

Cochrane Collaborationresults

0500

100015002000250030003500400045005000

3 15 27 39 51 63 75 102

156

Review Groups

Reviews

Reviews +protocols

Total results obtained per month since October 1993

Meta-analyses versus Cochrane Reviews

39 paper-based meta-analyses from MEDLINE versus 36 Cochrane Reviews from 1995

Meta-analyses Cochrane Rev. P<

In- and exclusion crit. 46% 97% 0.001Trial quality assessm. 31% 100% 0 .001Language restrictions 18% 0% 0 .01Updated in 1997 3% 50% 0 .001

(Jadad et a l., JAMA 1998;280:278-280)

The Cochrane Collaboration

• still only 14 years old

• needs at least another 10-12 years to

cover major parts of medicine

• with support from researchers and fund

holders the mission can be accomplished

Mean number of patients per intervention arm (SEM) in 383 randomised trials

published in Gastroenterology from 1964-2000 (Kjærgard et al. 2002)

Trial sequential analysis(TSA)

May be applied to meta-analyses

and more adequately assess

the available evidence

Jørn Wetterslev, Kristian Thorlund,

Jesper Brok, Christian Gluud

Documents

ECRIN - EURORDIS