1. Methodological and Statistical Considerations in Clinical Research Dr. Gloria Crispino, CStat CMath Copy Rights; Do not reproduce without authorization from the author

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. Copy Rights; Do not reproduce without authorization from the author

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 Profit Copy Rights; Do not reproduce without authorization from the author

5. Biomarkers Development Source: MMI – The Irish Biomarker Network Inaugural Workshop Copy Rights; Do not reproduce without authorization from the author

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 Copy Rights; Do not reproduce without authorization from the author

7. www.clinicaltrial.gov Copy Rights; Do not reproduce without authorization from the author

8. Ireland and Europe Copy Rights; Do not reproduce without authorization from the author

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 Copy Rights; Do not reproduce without authorization from the author

10. Understanding Research Design The link between the research question and the statistical methodology Research Question  Study Design  Statistical analysis Examples Copy Rights; Do not reproduce without authorization from the author

11. The flow Quantify the study A selection of endpoints – Primary, secondary – Exploratory Datasets and variables Study protocol Copy Rights; Do not reproduce without authorization from the author 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 Copy Rights; Do not reproduce without authorization from the author

13. Output: Regulatory Copy Rights; Do not reproduce without authorization from the author

14. Output: Large Research Organizations Copy Rights; Do not reproduce without authorization from the author

15. Output: pharma industry Copy Rights; Do not reproduce without authorization from the author

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 Copy Rights; Do not reproduce without authorization from the author

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. Copy Rights; Do not reproduce without authorization from the author