Clinical Trials: Introduction from an Epidemiologic Study Design Perspective

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Clinical Trials Introduction from an
Epidemiologic Study Design Perspective
Neal Simonsen
LSU

• Health Sciences Center

School of Public Health Stanley S. Scott
Cancer Center
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Experimental Study Design
Disease nonoccurrence
Exposed
Exposure assigned
Not exposed
OK
Unethical to perform experiments on people if
exposure is harmful
Not OK
http//www.epiet.org/course/Presentations/Presenta
tions202003/13-20CohortCase20control/13-20Coh
ortCase20control_files/frame.htm
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• A more-often-ethical alternative for conducting
  studies in human populations
• Observational Epidemiology allows capitalization
  on natural or unplanned experiments.
• Take advantage of groups who have been exposed
  for non-study purposes.

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What is a cohort?

• Group of individuals
• sharing same experience
• followed up for specified period of time
• Examples
• Birth cohort
• Cohort of guests at barbecue
• Occupational cohort of electricians

http//www.epiet.org/course/Presentations/Presenta
tions202003/13-20CohortCase20control/13-20Coh
ortCase20control_files/frame.htm
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Cohort Study
Exposed
Not Exposed
Develop Disease
Develop Disease
Do Not Develop Disease
Do Not Develop Disease
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Analytical Design of a Cohort Study
Incidence Rates of Disease
Then follow to see
whether Disease Disease does develops not
develop
Totals
a
Exposed a b a b a b c Not
exposed c d c d c d
First select
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Relative Risk
Risk in exposed Risk in non-exposed
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Potential Biases in Cohort Studies

• Bias in the assessment of the outcome
• If person assessing disease also knows exposure
• May be addressed by blinding
• Information bias
• Quality of information not comparable between
  exposed and non-exposed individuals

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Biases in Cohort Studies (Contd)

• Biases from non-response and losses to follow-up
• Non-participation / non-response and dropouts can
  complicate interpretations of findings
• Analytic bias
• Biases of epidemiologists/biostatisticians
  analyzing the data

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Relative merits cohort studies

• Advantages
• Clear temporal relationship
• Least susceptible to some forms of bias
• Can examine multiple predictors of outcome
• Efficient for rare exposures
• Useful when RCT infeasible, unethical

• Disadvantages
• No control over exposure (vs. RCT)
• Inefficient for rare or long-latent diseases
• Loss to follow-up threatens validity
• Potential bias in outcome ascertainment
• Relatively resource- and time-intensive

http//www.healthsystem.virginia.edu/internet/MTPC
I/Introcourse02/Lecture20620Bovbjerg.ppt
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Basic cohort design
http//www.healthsystem.virginia.edu/internet/MTPC
I/Introcourse02/Lecture20620Bovbjerg.ppt
Crucial comparison outcomes in persons with vs.
without predictor variable (or with different
levels of predictor)

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Basic trial design
http//www.healthsystem.virginia.edu/internet/MTPC
I/Introcourse02/Lecture20620Bovbjerg.ppt
Estimate of effect is rate (risk) of outcome in
treatment vs. control (e.g. risktreatment/riskc
ontrol)

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Two trial flavors

• Trials may be
• Non-randomized (in terms of assignment to
  treatment group)
• or
• Randomized
• Why be random?
• Sounds sooo unscientific

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Example of Bias due to Non-randomized Treatment
Assignment

• Study in Lanarkshire, 1930
• Treatment 1 3/4 pint raw milk/day (n5,000)
• Treatment 2 3/4 pint pasteurized milk/ day
  (n5,000)
• Treatment 3 no milk (n10,000)
• Response growth (increase in height and weight)

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The Results

• No milk group had significantly better growth
  than either milk treated group
• ? Giving kids milk is bad for their growth???

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The Problem and its Consequences

• Assignment initially randomized, but teachers
  could improve the assignment
• Results no milk group had better growth than
  either milk treated group
• Why?
• Teachers tended to assign poorer children to the
  milk treated groups

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Types of Associations
Real vs. Spurious Associations
A. Causal B. Due to Confounding
Milk supplementation
Milk supplementation
Observed Association
Observed Association
Poverty
Poorer Growth
Better Growth
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Gold Standard Basic randomized, controlled
clinical trial design
http//www.healthsystem.virginia.edu/internet/MTPC
I/Introcourse02/Lecture20620Bovbjerg.ppt
Estimate of effect is rate (risk) of outcome in
treatment vs. control (e.g. risktreatment/riskc
ontrol)

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Summary Epidemiologic Study Types

• Studies of group characteristics
• Ecologic
• Potential ecologic fallacy
• Studies of individual characteristics
• Cross-sectional
• Case-Control
• Cohort
• Intervention/Clinical Trial

within one group vs. another(s)