Methodological and statistical considerations in clinical research, by Dr Gloria Crispino, StatisticaMedica

1. Methodological and Statistical
Considerations in Clinical Research
Dr. Gloria Crispino, CStat CMath
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2. The translational Continuum
Source: Canadian Institute of Public Health
The inability to overcome the death valleys is due to multiple factors,
including the lack of methodological support.
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3. Drug Development
1 In 10,000 Succeed (to market/practice)
Average Time: 10-18Years
Average Cost: €500 Million to €2 billion
(<20% of sales)
100,000 Examined by FDA and
similar bodies
(Preclinical Evaluation)
100 Tested
in Humans
10 Marketed
Drugs
2 Drugs Return a ProfitCopy Rights; Do not reproduce without
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5. Biomarkers Development
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6. Medical Devices Development
Clinical Development
Basic
Research
Prototype
Discovery and
design
Pre-clinical
development
Exploratory FDA Approval
and Launch
Pivotal
Discovery
Diagnostic
Development
Pre-Validation & Validation Registration
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7. www.clinicaltrial.gov
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8. Ireland and Europe
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9. Type of studies
• Retrospective
– Historical Data
– Audits
– Pilots
• Prospective
– RCT
– Cohort studies
– Case-Control Studies
• Context of Clinical
Trials:
– Pharma
– Med Devices
– Diagnostics
– Food
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10. Understanding Research Design
• The link between the research question and
the statistical methodology
• Research Question  Study Design 
Statistical analysis
• Examples
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11. The flow
• Quantify the study
• A selection of endpoints
– Primary, secondary
– Exploratory
• Datasets and variables
• Study protocol
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1. Research Question
2. Study Design
3. Statistical Analysis
Plan

12. Evaluation of Statistics in Clinical Trials
• Statistical Analysis Plan
– Primary, secondary and exploratory endpoints/variables
• Clinical and commercial claims
• ITT and Per- protocol populations
• Regulatory requirements
• Data Management Plan
• Case Report Form (CRF)
• Descriptive summary Statistics, Inferential Statistics,
Statistical Modelling
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13. Output: Regulatory
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14. Output: Large Research Organizations
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15. Output: pharma industry
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16. Hierarchy of Evidence
• Evidence Hierarchy and evidence-based
medicine
• From Randomised Clinical Trials (RCT) to
expert opinion.
• Systematic reviews and Meta-Analysis
• Cohort Studies
• Case-Control studies
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17. International Guidelines on
Methodologies
Minimum accepted standards to guarantee entry to next phase
• EMEA & ICH Guidelines:
– ICH E9: Statistical Principles of Clinical Trials
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002928.pdf
• FDA, Clin-Stat Guidance 1988
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071665.pdf
• Good book:
Curtis E.A. and Drennan J: Quantitative Health Research – Issues
and Methods. McGraw Hill Education, Open University Press.
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