issues on design of clinical trials · superiority non-inferiority equivalence superiority shown...
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Issues on Design of Clinical Trials
Jimin Choi, PhD Senior Biostatistician
Clinical Research & Trial Center Dong-A University Hospital
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Outline
• Why do clinical trials?
• Types of hypotheses
• Design of clinical trials
• Sample size & power considerations
• How do we minimize bias?
• Concluding remark
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Why do clinical trials?
• To answer a clinical problem
• To gain new knowledge about a new or established treatment
• To support a “claim” - For gaining government regulatory approval
- For marketing a drug, device, or technique
Why do clinical trial?
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Principles of clinical trials
• Ethics
• Scientific validity and integrity
Why do clinical trial?
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What is step one?
• Start with a hypothesis
• Must be in the form of a statement
• The question must be “answerable”
• Choose the outcome you wish to measure
Why do clinical trial?
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Types of hypotheses Superiority Non-inferiority Equivalence
superiority shown
superiority not shown/ non-inferiority shown non-inferiority shown non-inferiority not shown Control -δ 0 Treatment better better Difference
Types of hypotheses
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Types of hypotheses Superiority Non-inferiority Equivalence
clinically superior not equivalent clinically equivalent not equivalent Control -δ 0 δ Treatment better better Difference
Types of hypotheses
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Non-Inferiority Challenges
• Requires high quality trial
• Treatment margin somewhat arbitrary
Types of hypotheses
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Commonly used designs
• Parallel design
• Factorial design
• Cross-over design
• Group sequential design
etc
Design of clinical trials
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Parallel Design Screen
Trt A
Randomize -
Trt B
• H0: A vs. B
• Advantage
– Simple, General Use
– Valid Comparison
• Disadvantage
– Few Questions/Study
Design of clinical trials
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Factorial Design
• Schema
Factor I
Placebo Trt B
Factor II
Placebo N/4 N/4
Trt A N/4 N/4
B vs. Placebo
A vs. Placebo
Design of clinical trials
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Factorial Design • Advantages
– Two studies for one
– Discover interactions
• Disadvantages – Test of main effect assumes no interaction
– Often inadequate power to test for interaction
– Compliance
• Examples – Physicians' Health Study (PHS) NEJM 321(3):129-135, 1989.
– Final report on the aspirin component
– Canadian Cooperative Stroke Study (1978) NEJM p. 53
Design of clinical trials
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Crossover Design
• Each patient receives both treatments.
• Order of treatment is randomized.
• Comparison is “within” patients not “between” patients.
Design of clinical trials
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Crossover Design
Period 1 Period 2
Drug A Drug B
Patients
Drug B Drug A
Design of clinical trials
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Crossover Design
Patients must complete both arms. Drug must be short acting. • Advantages: - Sample size reduced. - Allows a preference question
• Disadvantages: - Possible carry-over effect - Possible period effect (time)
Design of clinical trials
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Sequential Design
• Continue to randomize subjects until H0 is either rejected or “accepted”
• A large statistical literature for classical sequential designs
• Developed for industrial setting
• Modified for clinical trials
(e.g. Armitage 1975, Sequential Medical Trials)
Design of clinical trials
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Classical Sequential Design
• Continue to randomize subjects until H0 is either rejected or “accepted”
• Classic
Net
Trt
Effect
100 200 300
No. of Paired Observations
Trt Worse
Continue
Accept H0
Trt Better
Continue
-20
0
20
Design of clinical trials
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What is minimum number of patients to conduct a clinical trial?
• Sample size & power calculation
Sample size & power considerations
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Primary objective & primary endpoint
Definition of primary objective & primary endpoint is required.
Primary endpoint Test method
Categorical data Chi square test
Continuous data T test/ ANOVA
Survival data Log rank test
Sample size & power considerations
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Sample size calculation (1)
PC= 0.10 PT= 0.05 PC-PT= 0.05 (risk reduction rate: 50%) What is the required number of patients to detect 50% reduction of mortality rate ?
Sample size & power considerations
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nC=rnT
Sample size & power considerations
Sample size calculation (2)
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Sample size & power considerations
Sample size calculation (3) Mortality rate
Effect size Treatment Control Alpha Power n per group
5% 5% 10% 0.05 80% 435
5% 5% 10% 0.01 80% 647
4% 6% 10% 0.05 58% 435
3% 7% 10% 0.05 35% 435
4% 6% 10% 0.05 80% 721
3% 7% 10% 0.05 80% 1,356
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Change Sample size
alpha (type I error rate) ↓ ↑
Power ↑ ↑
Effect size ↑ ↓
Effect size ↓ ↑
Proportion near to 50% ↑
Sample size calculation (4)
Sample size & power considerations
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What is a clinical trial’s greatest enemy?
• Bias
How do we minimize bias?
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How do we minimize bias?
• Make sure groups are equivalent
=> Randomization
• Standardize outcome assessment
=> Blinding
• Unbiased data analysis
=> ITT principle
How do we minimize bias?
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Concluding remark
It is highly recommended to co-work with biostatistician from the early stage of planning clinical trials.
Concluding remark
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Thank you for your attention.