Clinical Research and the Importance of Collaboration www. phri .ca
Picture if you can..1993 www. phri .ca
HOPE – A large, simple, trial N Pts N Sites N Countries In the beginning ( 1993 ) 6,500 130 10 …and then (1994) 8,000 160 15 But finally (1995) 9,541 267 19 Collaboration! www. phri .ca
www. phri .ca
(Some of) the studies that followed 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 www. phri .ca
www. phri .ca
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 www. phri .ca
How can the process be improved? Common issues plaguing study conduct • Individual case safety reporting • Event adjudication • Excessive monitoring www. phri .ca
Streamlining: Safety Reporting • First studies to use the triple “and” - serious and unexpected and associated • National Leaders defend approach: • Locally (ethics) • Nationally (regulatory bodies) www. phri .ca
Streamlining: Adjudication www. phri .ca
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) www. phri .ca
Streamlining: Monitoring www. phri .ca
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) www. phri .ca
Collaborating to resolve fundamental clinical trial issues 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 www. phri .ca
Which led to other initiatives • Initiatives to Streamline Clinical Trials – Canada • India – Efforts with DCGI • MoreTrials (http://moretrials.net) www. phri .ca
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 www. phri .ca
IMPI Tuberculous Pericarditis Trial RECRUITMENT BY COUNTRY 1014 Total N = 1400 N 133 90 62 29 23 26 23 www. phri .ca
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 www. phri .ca
Randomization N=5,713 6000 5000 4000 N Participants 3000 Philippines 2000 1000 India 0 www. phri .ca Canada Colombia Malaysia Tanzania Bangladesh Tunisia Indonesia
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) www. phri .ca
Key Performance Indicators (Tool Kit) Initial assessment, Secondary diagnosis & Mobilization prevention (AF, documentation lipids) Physiological management (FeSS) Multidisciplinary Management ICH teamwork (fever, sugar, swallowing) Discharge planning & Bowel & bladder caregiver Anti-hrombotics Pressure care 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) www. phri .ca
Rwanda National Champion: Gerard Urimubenshi, PT 2 centres recruiting (Site Champions in each), 1 st pt July 12, 2017 Recruitment as expected; intervention phase to begin 35 30 25 *3 patients N Participants refused 20 Kigali 101 15 Butare 102 *1 patient 10 refused 5 0 jul-17 aug-17 sep-17 okt-17 Approx. weekly 1/week 3/week 2/week 1/week www. phri .ca recruitment 1/week 1/week 1/week 0.25/week rate
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! www. phri .ca
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