Bureaucratic obstacles to clinical
trials: in the public interest?
Rory Collins
BHF Professor of Medicine & Epidemiology
Clinical Trial Service Unit
& Epidemiological Studies Unit
University of Oxford
Stated aim of EU Directive on Clinical Trials
Article 1: "Compliance with this good
practice provides assurance that the
rights, safety and well-being of trial
subjects are protected, and that the
results of the clinical trials are credible."
What is the evidence for this claim?
Criteria for a good trial
• Ask an IMPORTANT question
• Answer it RELIABLY
Unanticipated consequences of good intentions
• MODERATE effects of treatments can
have LARGE effects on public health
• RELIABLE assessment of MODERATE
effects on mortality and major morbidity
requires LARGE RANDOMISED trials
• Consequently, bureaucratic obstacles to
LARGE RANDOMISED trials may well
inadvertently REDUCE public safety
ISIS-2: 2 x 2 “factorial” study of iv streptokinase
and of oral aspirin in acute MI (17,000 patients)
Meta-analysis of small fibrinolytic trials (1959-85)
Pharmacovigilance in randomised trials
• LARGE effects on RARE outcomes may
be detected by the reporting of Suspected
Unexpected Serious Adverse Reactions
(SUSARS) required in trials by regulators
– but this does not require randomisation
• But, reliable assessment of MODERATE
effects on COMMON outcomes does need
LARGE-SCALE RANDOMISED evidence
RELIABLE assessment of MODERATE hazards:
large-scale randomised meta-analysis of the effects
of COX-2 inhibitors on major vascular events
Coxib vs.
No. of
trials
Events/person-years
Allocated
Allocated
Coxib
Other
Ratio of annual event rates
Coxib : Other
Placebo
91
209/11584
(1·8%/y)
106/8689
(1·2%/y)
1·41 ( SE 0·14)
Naproxen
38
180/15980
(1·1%/y)
78/10755
(0·7%/y)
1·56 ( SE 0·17)
Non-naproxen NSAID 42
148/16558
(0·9%/y)
127/12098
(1·0%/y)
0·86 ( SE 0·12)
2·5 5·0 10
0·1 0·25 0·5 1·0
Coxib better
Other better
2
Heterogeneity: c 2 = 12·9; p = 0·002
CR-UK assessment of impact of Clinical Trials
Directive on UK non-commercial cancer trials
(European Journal of Cancer 2006)
• Doubling in costs of running non-commercial
cancer trials and 6-12 month delays to starting
• Major concerns about correct interpretation
due to lack of central guidance, lack of clarity
regarding interpretation of guidance notes, and
increased documentation
• Clinical trial units unable or unwilling to start in
non-UK centres due to different interpretations
in different European countries
UK NHS R&D: Increasing trial approval times
Days
Measure
2006
2007
2008
Notification to R&D sign off
66
111
95
R&D sign off to first patient visit
35
62
62
166
204
213
First submission to first patient visit
Report for the Ministerial Industry Strategy Group (2008)
Over-interpretation of NHS Research Governance
requirements for pharmacovigilance
“… you must report to the Research
Management & Governance Unit
any serious adverse event occurring
during the study….”
quote from the Research Governance
lead of a local Primary Care Trust
Cost per patient in phase III trial
with 10 visits over 10 weeks
Report for the Ministerial Industry Strategy Group (2008)
Quote from Bob Temple (US FDA): “EU Directive
on Clinical Trials is Europe’s gift to the USA”
Global patient enrolment: 2000 vs 2006
North
America
2000
41%
EU Core
Europe Non-Core
EU Accession
2000
21%
8%
4%
2000
6%
2006
2%
UK
2006
14%
13%
7%
SE Asia &
W Pacific
2000
2%
2006
39%
ME &
Africa
Latin
America
2000
3%
2000
2%
2006
2%
2006
39%
Report for the Ministerial Industry Strategy Group (2008)
2006
7%
ICH GCP: Guidance on monitoring
“… extent and nature of monitoring should be
based on considerations such as the objectives,
purpose, design, complexity, blinding, size and
endpoints of the trial. In general there is a need for
on-site monitoring before, during and after the trial;
…[but] central monitoring…can assure appropriate
conduct of the trial in accordance with GCP”
ICH GCP Section 5.18.3
Central monitoring by coordinating centre
Record checks for:
• Patient eligibility (eg, pathology report to substantiate diagnosis)
• Patient existence (eg, ONS flagging or imaging investigation)
• Outcome (eg, ONS flagging for death; investigation results)
Statistical checks for:
• Missing or invalid data (eg, range checks)
• Calendar checks (eg, dates of recruitment)
• Unusual patterns (eg, digit preference, rounding or unusual
frequency distribution)
• Reporting rates (eg, frequency of adverse events or missing data)
• Repeated measures (eg, variability and within-individual changes)
MRC/DH joint project (www.cl-toolkit.ac.uk)
ESPS-2: Potential problem at one site
identified by central statistical monitoring
Unusually rapid recruitment
Regularity of follow-up visits
(inc. weekends & holidays)
Reduced variability of data (eg, BP)
Better study treatment compliance
Lower incidence of adverse events
Poor correlation between measurements
at different follow-up visits
ESPS-2: Confirmation of problem
by central assay of blood samples
Both DIP & ASA were in all samples (rather
than expected 25%)
DIP levels were either trace or very high (&
different from other centres)
ASA levels were incompatible with low-dose
aspirin regimen
Plasma protein polymorphism measurement
showed each of 90 samples was from same
mixture of plasma from several persons
ESPS-2: Failure to detect fraud
during special audit site visit by
Good Clinical Research Practices Ltd
“The auditors were not able to
uncover major anomalies in the
data collected by this centre.”
ESPS-2 report,
June 1996
Claims of risks to patients in clinical trials
“Trials of new medicines ….. are so
badly flawed that they endanger the
health of the patients ….. according to
scientists who have been auditing
them in confidence for 10 years …..
Good Clinical Research Practices is
called in by pharmaceutical companies
to establish whether trials meet
international standards”
Guardian July 1999
“Possible” conflicts of interest
Petitions for compulsory winding-up
Week ending 18 June 1999
(www.insolvency.co.uk)
14/07/99 Good Clinical
Research Practices Ltd
“….. fraud in clinical trials is so rare and …..
generally inconsequential, that the public
may be far more misguided by studies that
are poorly designed, wrongly analysed and
inappropriately reported than by fraud”
ISCB subcommittee on fraud
Stat Med 1999
Report of the ISCB subcommittee on misconduct
in clinical trials (Statistics in Medicine 1999)
Misconduct is unlikely to affect study results if any of the
following conditions hold:
• The misconduct is limited to a few investigators (eg, one
centre in a multicentre setting) and/or to a few data items;
• The misconduct bears on secondary variables that have
little or no effect on the primary endpoint of the study; or
• The misconduct affects all treatment groups equally, and
hence does not bias the results of the study.
NB: Misconduct committed without regard to the treatment
assignments (for example, prior to randomization or in
double blind trials) generates noise but no bias.
“The growing number of regulations
….. may also have the unintended
consequence of making trials ever
more complex ….. such complexity
may be counterproductive and may
pave the way to fraud”
ISCB subcommittee on fraud
Stat Med 1999
Proliferation
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of trials
Second Conference on Sensible Guidelines
for the Conduct of Clinical Trials
5-6 September 2009
St Anne’s College, Oxford
For details, contact:
[email protected]
Proceedings of First Conference:
Clinical Trials 2008; 5 (1): 38-84