investigator-driven clinical research · the clinical investigator • clinical expertise -...
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Investigator-Driven Clinical ResearchA McMaster Perspective
John EikelboomMcMaster University
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Key Questions
1. What does it take to be a clinical investigator?
2. Where do clinical research questions come from?
3. What else is required for successful investigator-driven clinical research?
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What does it take to be a clinical investigator?
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Clinical Investigator in the 1960s
Clinical Practice
LaboratoryResearch
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Spectrum of Research
Basic Clinical Epidemiology
1960s
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Spectrum of Research
Basic Clinical Epidemiology
Basic ClinicalClinical
EpidemiologyClassical
Epidemiology
1960s
2010
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Clinical Investigator in Contemporary Times
Clinical Problem Drives the Research
BasicResearch
Clinical Epidemiology
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The Clinical Investigator
Passionate Creative Clinical ExpertiseTraining in
Methodology
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Passionate Creative
The Clinical Investigator
• Clinical expertise - patients are your laboratory
• Methodologic training – Clinical Epidemiology and Biostatistics Program
“Serve apprenticeship with an outstanding researcher and mentor”
Clinical ExpertiseTraining in
Methodology
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Where do (good) clinical research questions come from?
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The Question
If the question can be answered, will it provide:
• New information that will change practice?
• New information that will improve understanding of pathophysiology?
• Hypothesis-generating information that will form the basis of a more definitive study?
• Confirmatory information?
• Descriptive information?
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Where do Clinical Research Questions Come From?
Clinical Experience
TheLiterature
ObservationalStudies
UnexpectedRCT Findings
The Research Question
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Question from Clinical Experience
• Aspirin is effective for prevention of cardiovascular events in ACS
• Some ACS patients receive low dose aspirin while others receive higher doses
Is 300-325 mg/d more effective than 100 mg/d for prevention of recurrent cardiovascular events in patients with ACS?
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Question fromUnexpected RCT findings
• More intensive antithrombotic therapy in patients with ACS reduces the risk cardiovascular events but at the cost of more bleeding
• In the OASIS-5 trial, fondaparinux compared with enoxaparin reduced the risk of recurrent vascular events and reduced bleeding.
Why did fondaparinux reduce bleeding?
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Question from Observational Studies
• Homocysteine levels in blood independently predict cardiovascular events
• Blood levels can be readily lowered with safe and inexpensive B-vitamin treatment
Does treatment with B-vitamins prevent cardiovascular events?
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What (else) is required to reliably answer a good
clinical question?
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A Tale of Two Cities
Characteristic Perth, Australia Hamilton, Canada
Country Population 20 million 30 million
Regional Population 1.5 million 0.5 million
Medical Schools 1 1
Researchers Few Critical mass
Training Capacity Limited CEB program
Expert Personnel Few Extensive pool
Infrastructure Limited Well established
Funding Challenging Substantial
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PHRI
TaARI
CE & BTrials Network
TestHypotheses
Explore mechanisms
Large registries, Epidemiologic studies,
RCTs, KT projects
Moderate-sizedepidemiologic studies,
randomised trials
Training ofClinician Investigators
BiostatisticiansCoordinators
Training ofClinician Investigators
BiostatisticiansCoordinators
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Challenges of Current Randomised Controlled Trials
• Restrictive regulatory requirements
• Complex trial design
• Limited expertise, infrastructure, training
• Lack of trial funding
→ randomized trials dominated by industry-sponsored studies
→ neglect of diseases, interventions , outcomes, populations, mechanisms
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Synergies Between Industry and Investigator-initiated Research
• Factorial design– Address generic questions e.g., vitamin E in the
HOPE trial, aspirin dose in the CURRENT trial
• Scientific substudies– Explore diagnostic, pathophysiologic or prognostic
questions e.g., pharmacogenomics of warfarin therapy in the RE-LY trial
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Synergies Between Industry and Investigator-initiated Research
• Implement epidemiologic studies concurrently with RCTs– DREAM trial and EpiDREAM study
• RCTs inform the design of future studies– POISE-1 led to the VISION cohort study
– RE-LY trial and RE-LY ABLE registry
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Potential Solutions
• Simple trial design
• Streamline trial regulations
• Pragmatic monitoring
• Innovative trial design
• Long term investment in expertise, infrastructure and training
• Increased funding for investigator-initiated randomised controlled trials
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Conclusion
• Trained clinical investigator
• A good question
• Expert personnel
• Research Infrastructure
• Funding
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Jack HirshProfessor Emeritus
McMaster University
“….be passionate about your
research, train with the best in your
area of interest and spend as long as it
takes….”