clinical research and the importance of collaboration · hope –a large, simple, trial n pts n...
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Clinical Research and the Importance of Collaboration
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Picture if you can..1993
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HOPE – A large, simple, trial
N Pts N Sites N Countries
In the beginning (1993) 6,500 130 10
But finally (1995) 9,541 267 19
…and then (1994) 8,000 160 15
Collaboration!
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Study Drug Indication
HOPE Ramipril Prevention of MI, Stroke & death
RESOLVD Cand/Metop Heart failure
OASIS-4 Clopidogrel Acute Coronary Syndrome
OASIS-5 Fondaparinux Non-ST Elevation MI
OASIS-6 Fondaparinux ST Elevation MI
ONTARGET/TRANSCEND Telimisartan Prevention of CVD
RELY Dabigatran Prevention of stroke in Atrial Fibrillation
AVERROES Apixaban Prevention of stroke in Atrial Fibrillation
(Some of) the studies that followed
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Key characteristics of (most) PHRI studies
• Scientifically interesting question
• Collaborate with National Leaders:•Expert trialists’ and not just key opinion leaders
•Member of the Steering Committee
• Involved in developing protocol, CRFs, study procedures
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How can the process be improved?
Common issues plaguing study conduct• Individual case safety reporting• Event adjudication• Excessive monitoring
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Streamlining: Safety Reporting
• First studies to use the triple “and” - serious and unexpected and associated
• National Leaders defend approach:• Locally (ethics)• Nationally (regulatory bodies)
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Streamlining: Adjudication
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Event Adjudication
• No effect on study outcomes/conclusions
• Is it worthwhile? How can we streamline?• Use event definitions that closely resemble usual practice • Only adjudicate those events which don’t meet the criteria• Ask National Leaders to adjudicate (in local language)
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Streamlining: Monitoring
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Monitoring
• Risk based approach
• Used in APOLLO (2011), HOPE-3, TIPS-3 and COMPASS• Implemented through National Leader’s office
•ADAMON study (2017) showed risk-based monitoring was non-inferior to extensive monitoring• At best, on site may reduce major GCP findings by 8%
•Congruent with recent ICH E6 R2 (revision)
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Collaborating to resolve fundamental clinical trialissues
2007 – Duke, Oxford and PHRI organize the first Sensible Guidelines meeting•Academics, regulators, industry sponsors invited
•Objective is to identify biggest barriers to trial conduct
•8 publications
2009, 2012 Repeat Workshops
2017 ICH E6 modified
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Which led to other initiatives
• Initiatives to Streamline Clinical Trials – Canada
• India – Efforts with DCGI
• MoreTrials (http://moretrials.net)
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Collaboration: Low & middle income countries
• INTERHEART, INTERSTROKE, INTERBLEED
• PURE (~180,000)
• IMPI (Investigation of the Management of Pericarditis)
• No effective treatment for TB pericarditis: Anti-
inflammatory may work
• Collaboration with University of Cape Town, Bongani
Mayosi, Mpiko Ntsekhe
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IMPI Tuberculous Pericarditis Trial
RECRUITMENT BY COUNTRY
90 13323 26 62 29 23
1014N
Total N = 1400
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Collaboration: Low & middle income countries
• Interheart, Interstroke, Interbleed
• PURE (~180,000)
• IMPI
• TIPS-3 (The Indian Polycap Study -3)• Polycap in those at moderate risk of CV disease
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Randomization
0
1000
2000
3000
4000
5000
6000
N P
arti
cip
ants
Canada Colombia Malaysia Tanzania Bangladesh Tunisia Indonesia
India
Philippines
N=5,713
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Collaboration: Low & middle income countries
• Interheart, Interstroke, Interbleed
• PURE (~180,000)
• IMPI
• TIPS-3
• OSCAIL: Organized Stroke Care Across Income Levels• South Africa, Rwanda, India (Uganda, Sri Lanka, Nigeria)
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Key Performance Indicators (Tool Kit)
Initial assessment, diagnosis &
documentation
Physiologicalmanagement (FeSS)
(fever, sugar, swallowing)
Bowel & bladder
Pressure careAnti-hrombotics
Multidisciplinary teamwork
MobilizationSecondary
prevention (AF, lipids)
Management ICH
Discharge planning & caregiver
involvement
Change from a usual frequency of 5-12% (based on INTERSTROKE) to over 25% in each country (i.e. at least one in four patients)
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RwandaNational Champion: Gerard Urimubenshi, PT
2 centres recruiting (Site Champions in each), 1st pt July 12, 2017
Recruitment as expected; intervention phase to begin
0
5
10
15
20
25
30
35
jul-17 aug-17 sep-17 okt-17
N P
arti
cip
ants
Kigali 101
Butare 102
*3 patients refused
*1 patient refused
Approx. weekly recruitment rate
1/week1/week
3/week1/week
2/week1/week
1/week0.25/week
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Collaboration today..
Necessary for:• Detecting modest but worthwhile treatment effects
• Accurate estimates of treatment effects across different ethnicities and health care systems
• Efficient knowledge translation
Progressive• Two way street
And it is an incredibly rewarding experience!