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Methodological and Statistical Considerations in Clinical Research

Dr. Tim Grant, CStat CSci

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Types of Evidence

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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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Drug Development

1 In 10,000 Succeed (to market/practice)

Average Time: 10-18YearsAverage Cost: €500 Million to €2

billion (<20% of sales)100,000 Examined by FDA and similar bodies

(Preclinical Evaluation)

100 Testedin Humans

10 Marketed Drugs

2 Drugs Return a Profit

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Biomarkers Development

Source: MMI – The Irish Biomarker Network Inaugural Workshop

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Medical Devices Development

Clinical Development

Basic Research

PrototypeDiscovery and

design

Pre-clinical development Exploratory FDA Approval

and LaunchPivotal

Discovery

Diagnostic Development

Pre-Validation & Validation Registration

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www.clinicaltrial.gov

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Ireland and Europe

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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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Understanding Research Design

• The link between the research question and the statistical methodology

• Research Question Study Design Statistical analysis

• Need to Remove Bias

• Examples

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The flow

• Quantify the study• A selection of endpoints– Primary, secondary– Exploratory

• Datasets and variables• Study protocol

1. Research Question

2. Study Design

3. Statistical Analysis Plan

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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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Output: Regulatory

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Output: Large Research Organizations

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Output: pharma industry

International Guidelines on Methodologies

Minimum accepted standards to guarantee entry to next phase• EMEA & ICH Guidelines:

– ICH E9: Statistical Principles of Clinical Trialshttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002928.pdf

• FDA, Clin-Stat Guidance 1988http://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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