CHS502
Unit IV-1
Randomized Blinded Trial
Ahmed A. Mirza, PhD
Unit IV Outline
Outline:
•Designing randomized blinded trial
1.Selecting intervention
2.Selecting control
3.Selecting outcome measurements
4.Selecting participants
•Measuring baseline variables
•Randomizing and blinding
1.Random assignments
a)Blocked randomization
b)Stratified blocked randomization
c)Matched pairs randomization
2.Blinding
•Factorial design
1.The basic 2 × 2
2.Factorial design variations
3.Cluster randomization
•Nonrandomized between-group design
•Within-group design
•Pilot clinical trials
•Conducting clinical trials
1.Follow-up
2.Adjudicating outcome
3.Monitoring
4.Analyzing the results
•Designing studies for medical tests
1.General issues
a)Gold standard
b)Spectrum of severity of
diseases
c)Other sources of variations
d)Blinding
e)Costs vs. charges
•Test reproducibility
•Test accuracy
1.Sensitivity and specificity
2.Positive and negative predictive
values
3.Receiver operating characteristics
(ROC) curves
• This is not an observational study design
• This is an intervention
• Probably the best to establish causality
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Random: to eliminate confounders
Blinded: to eliminate observer effects
• be time consuming and laborious
• Can be expensive
• Usually is the last step of research after
strong evidence and support
General design
• Select a sample from the intended
population
• Measure the dependent and baseline
variables
• Randomly assign subjects and controls
• BLINDLY administer the intervention (e.g.,
drug and placebo)
• Follow-up by measuring the outcome
(WHILE BLINDED to group assignment)
Intervention
• It is the critical first step
• Must consider
– Effectiveness and safety
• Establishing the lowest effective dose with least risks
– Dose
– Number of interventions
• Single (keeps it easy)
• Multiple
Using estrogen + progestin therapy increased risk of breast
cancer… which one??
Controls
• Control will receive no intervention
– Placebo
• The problem is ethical: How can you
withhold treatment?
– Give standard care to all + new treatment, this
is called “co-intervention”
– Reduces causality
– If the new treatment is proven effective in
premedical trials then offer an equivalence trial
(controls take approved intervention while test
subjects take the intervention being tested
Outcome measurements
• Clinical outcome: best way to assess the
intervention
– Quality of life
– Better post-intervention
• Renal function
• Hepatic function
• Days in the hospital
– Surrogate markers
• Values that reflect the clinical outcome and is a is
immediately affected by the intervention – great
predictor
– BUN/Creat, AST/ALT, ...
– Adverse effects
Selecting subjects
• Inclusion criteria
– Not too many that will cost too much
– Too little not enough power
– Select patients that will show the greatest
benefit
• Stratification:
• Enrolling subgroups according to a predicted
outcome
• Exclusion Criteria
– Exposure to treatment/placebo might be
harmful
• Allergies
– Co-intervention
• Existing treatment might interfere with new one
– Adherence
• Unlikely to adhere or continue the study
– Moving
– Problems with the subject
• Mental state
Measuring baseline variables
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Collect all possible data about the subjects
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Useful for later generalizability
Comparability
Reduction of confounders
Risk factors that might effect subgroups
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Can be used to subgroup subjects to
establish “effect modification” or
“interaction”
Showing that alendronate had effect on
women with low bone density but not on
women with high bone density.
Randomizing
• Baseline examination
• Consent
• Randomly assign by computerized
algorithm
Must follow rigorous precautions to prevent
tampering with subject and control
assignment. Observers can be very bias.
Best is just a simple randomization to an
equal ratio between subjects and control
To increase power to smaller studies
Blocked Randomization:
Stratified blocked randomization:
Unequal allocation
Randomization of matched pairs
(read on page 157)
Blinding
• Blinding:
– Subject
– Observer
• Multiple sclerosis study: patients received
plasma exchange/medication vs. sham
plasma exchange and placebo. Physicians
who were blinded show no difference,
physicians who were not blinded concluded
significant difference in outcome.
If you have a problem with…
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Chance (as discussed before)
Bias (as discussed before)
Effect-Cause (not possible)
Confounding
– Prerandomization (Randomization)
– Postrandomization (Blinding)
What if you CANNOT blind?
Control confounders as much as possible
Have outcome measured by different observer
than ones who worked with the subjects
CHS 502
Unit IV-2
Alternative Trial Design
Ahmed A. Mirza, PhD
Factorial Design
Aims to answer more than one question at the
same time using a single cohort of participants
Treating the sample with both drugs A & B, while
maintaining the presence of placebo a & b
A total of 4 groups receiving 4 combination of the
drugs (AB, Ab, aB, ab)
 Steps, like the general steps of a randomized
blinded trial covered previously, however add:
Analysis: compare the two groups receiving drug
A with the ones receiving placebo a. Then
compare the ones receiving A vs B, and so on.
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Advantages
 Can be very efficient
 Two trials for the price of one
Disadvantages
 Possible interaction between
interventions, which reduces power
 Sample must be appropriate for both
interventions
Group or cluster randomization
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Rather than assigning individuals, assign whole
groups to receive, or not to receive, the
intervention.
Naturally occurring groups such as teams,
families, classes
It reduces subject bias
More feasible and cost effective
Will reduce power
More complex stats and sample size estimation
Nonrandomized Between-Group
Design
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Such studies are less effective than
randomized trials. Why?
Can use “adjustment” to deal with
variations amongst base-line variables
Nonrondomized studies show greater
benefit of the intervention, however
confounders might introduce a statistical
weakness.
Within-Groups Designs
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Time-Series design:
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Measurements are made before and after each
subject receives the intervention
The subject plays both rolls of control and case
Lack of concurrent control
Learning effects: the subject being exposed to
the assessment twice (virtual microscopy)
Regression to the mean: due to random
variations (blood pressure)
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Useful to do is starting and stopping the
intervention.
Provide stronger support that changes are due
to the intervention (Statin effects on LDLCholesterol)
The crossover design
Similar to what we discussed before
 Switching the control group to the test group
and test group to the control group
Groups taking the drug will take a placebo and the
group taking the placebo will take the drug.
 Problem, “carryover effects”, the time it takes
the drug to clear the system and no longer have
any effects.
 Introduce a “washout” period
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Stages of new Therapy
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Preclinical: Cell culture and animals
Phase I: Unblinded, uncontrolled, check for
safety
Phase II: small randomized blinded study, check
for dose and clinical outcome and
Phase III: Large randomized and blinded study,
check for clinical outcome
Phase IV: After approval. Done by pharm
companies to assess side effects and other
uses for the intervention.
Designing Studies for Medical
Tests
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How reproducible is the test?
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How accurate is the test
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Intra- and inter-observer
Does it match the gold standard
How often does the test effect clinical decision?
What are the costs, risks associated with the
test?
How is going to improve the clinical outcome?