ecrin - eurordis
TRANSCRIPT
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?
• Network of national networks
• Infrastructure to facilitate more research
•• Infrastructure to facilitate better researchInfrastructure to facilitate better research
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?
• Network of national networks
• Infrastructure to facilitate more research
•• Infrastructure to facilitate better researchInfrastructure to facilitate better research
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?
• Network of national networks
• Infrastructure to facilitate more research
•• Infrastructure to facilitate better researchInfrastructure to facilitate better research
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
Proportion of randomised trials in GASTRENTEROLOGY
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
Proportion of randomised trials in GASTRENTEROLOGY
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