Clinical Trials: Introduction from an Epidemiologic Study

Design Perspective

Clinical Trials: Introduction from an Epidemiologic Study

Design Perspective

Health SciencesHealth Sciences CenterCenter

School of Public Health &

Stanley S. Scott Cancer Center

LSU

Neal SimonsenNeal Simonsen

Experimental Study Design

Exposed

Not exposed

Disease nonoccurrence

Unethical to perform experiments on people if exposure is harmful

Exposure assigned

http://www.epiet.org/course/Presentations/Presentations%202003/13-%20Cohort&Case%20control/13-%20Cohort&Case%20control_files/frame.htm

OK

Not OK

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.

What is a cohort?

Group of individuals Group of individuals ……sharing same experience sharing same experience ……followed up for specified period of timefollowed up for specified period of time

Examples:Examples: Birth cohortBirth cohort Cohort of guests at barbecueCohort of guests at barbecue Occupational cohort of electriciansOccupational cohort of electricians

http://www.epiet.org/course/Presentations/Presentations%202003/13-%20Cohort&Case%20control/13-%20Cohort&Case%20control_files/frame.htm

Cohort Study

Exposed Not Exposed

DevelopDisease

Do NotDevelopDisease

DevelopDisease

Do NotDevelopDisease

First select

Exposed a b a + b a + b

cNot exposed c d c + d c + d

Then follow to see whether…Disease Disease doesdevelops not develop

a

Totals

Incidence Rates of Disease

Analytical Design of a Cohort Study

Relative Risk

Risk in exposedRisk in non-exposed

Potential Biases in Cohort Studies

Bias in the assessment of the outcomeBias in the assessment of the outcomeIf person assessing disease also knows If person assessing disease also knows

exposureexposureo May be addressed by blindingMay be addressed by blinding

Information biasInformation biasQuality of information not comparable Quality of information not comparable

between exposed and non-exposed between exposed and non-exposed individualsindividuals

Biases in Cohort Studies (Cont’d) Biases from non-response and losses to Biases from non-response and losses to

follow-upfollow-upNon-participation / non-response and Non-participation / non-response and

dropouts can complicate interpretations dropouts can complicate interpretations of findingsof findings

Analytic biasAnalytic biasBiases of epidemiologists/biostatisticians Biases of epidemiologists/biostatisticians

analyzing the dataanalyzing the data

Relative merits: cohort studiesAdvantagesAdvantages Clear temporal Clear temporal

relationshiprelationship Least susceptible to some Least susceptible to some

forms of biasforms of bias Can examine multiple Can examine multiple

predictors of outcomepredictors of outcome Efficient for rare Efficient for rare

exposuresexposures Useful when RCT Useful when RCT

infeasible, unethicalinfeasible, unethical

DisadvantagesDisadvantages No control over exposure No control over exposure

(vs. RCT)(vs. RCT) Inefficient for rare or Inefficient for rare or

long-latent diseaseslong-latent diseases Loss to follow-up Loss to follow-up

threatens validitythreatens validity Potential bias in outcome Potential bias in outcome

ascertainmentascertainment Relatively resource- and Relatively resource- and

time-intensivetime-intensivehttp://www.healthsystem.virginia.edu/internet/MTPCI/Introcourse02/Lecture%206%20Bovbjerg.ppt

Basic cohort design

Crucial comparison: outcomes in persons with vs. without predictor variable (or with different levels of predictor)

Study population

Predictorpresent

Predictorabsent

NoYes NoYes

follow-up period

outcome of interest

no investigator control

http://www.healthsystem.virginia.edu/internet/MTPCI/Introcourse02/Lecture%206%20Bovbjerg.ppt

Basic trial design

Estimate of effect is rate (risk) of outcome in treatment vs. control (e.g. risk[treatment]/risk[control])

Study population

Treatment No treatment(usual care, placebo)

NoYes NoYes

follow-up period

outcome of interest

assignment by investigator

http://www.healthsystem.virginia.edu/internet/MTPCI/Introcourse02/Lecture%206%20Bovbjerg.ppt

Two trial flavors

Trials may be:Trials may be:

Non-randomized (in terms of assignment to Non-randomized (in terms of assignment to treatment group)treatment group)

oror

RandomizedRandomized

Why be random?Why be random?

o [Sounds sooo unscientific…][Sounds sooo unscientific…]

Example of Bias due to Non-randomized Treatment Assignment Study in Lanarkshire, 1930Study in Lanarkshire, 1930

Treatment 1: 3/4 pint raw milk/day (n=5,000)Treatment 1: 3/4 pint raw milk/day (n=5,000) Treatment 2: 3/4 pint pasteurized milk/ day Treatment 2: 3/4 pint pasteurized milk/ day

(n=5,000)(n=5,000) Treatment 3: no milk (n=10,000)Treatment 3: no milk (n=10,000)

Response = growth (increase in height and Response = growth (increase in height and weight)weight)

The Results

No milk group had significantly better No milk group had significantly better growth than either milk treated groupgrowth than either milk treated group

Giving kids milk is bad for their growth???Giving kids milk is bad for their growth???

The Problem and its Consequences

Assignment initially randomized, but… teachers Assignment initially randomized, but… teachers could “improve” the assignmentcould “improve” the assignment

Results: no milk group had better growth than Results: no milk group had better growth than either milk treated groupeither milk treated group

Why?Why?

Teachers tended to assign poorer children to the Teachers tended to assign poorer children to the milk treated groupsmilk treated groups

Types of Associations

Milk supplementation

A. Causal B. Due to Confounding

Real vs. Spurious Associations

Milk supplementation

BetterGrowth

PoorerGrowth

PovertyObserved Association

Observed Association

“Gold Standard”: Basic randomized, controlled clinical trial design

Estimate of effect is rate (risk) of outcome in treatment vs. control (e.g. risk[treatment]/risk[control])

Study population

Treatment No treatment(usual care, placebo)

NoYes NoYes

follow-up period

outcome of interest

random assignment by

investigator

http://www.healthsystem.virginia.edu/internet/MTPCI/Introcourse02/Lecture%206%20Bovbjerg.ppt

Summary: Epidemiologic Study Types Studies of group characteristicsStudies of group characteristics

EcologicEcologicPotential ecologic fallacyPotential ecologic fallacy

Studies of individual characteristics*Studies of individual characteristics*Cross-sectionalCross-sectionalCase-ControlCase-ControlCohortCohortIntervention/Clinical TrialIntervention/Clinical Trial

* [~within one group vs. another(s)]* [~within one group vs. another(s)]