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Copyright 2008, The Johns Hopkins University and Mary Foulkes. All rights reserved. Use of these materials
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http://creativecommons.org/licenses/by-nc-sa/2.5/http://creativecommons.org/licenses/by-nc-sa/2.5/8/13/2019 Biomedical Statistics Johns Hopkins
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Study Designs, Objectives, and Hypotheses
Mary Foulkes, PhDJohns Hopkins University
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Section A
Variations in Study Designs
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Many Designs Available
Parallel Cross-over
Factorial
Cluster
Others
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Categories of Trials
Phases Control groups
Chronic vs. short-term treatment
Single vs. multiple centers
Exploratory vs. confirmatory
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Study Designs
Focus on trials intended to provide primary evidence of safety andefficacy (pivotal trials)
Regulations permit substantial flexibility (adequate and well-
controlled trials)
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Selecting a Study Design
What are the objectives? What are the expectations?
Major advance Modest advance
Reduction in side effects What are the practicalities?
Available population
Relevant population Potential impact on medical practice
Ability to blind/mask
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Parallel Design
Classical clinical trial approach Two study groups
Randomized assignment
Randomization
Treatment A
Evaluation of
Outcomes
Treatment B
Adapted from Tinmouth A, Hebert P. Interventional trials: an overview of design alternatives. Transfusion. 2007;47:565-67.
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Factorial Designs
Evaluates multiple factors simultaneously 2 X 2 most practical, but little used
Sometimes a combination cannot be given (incomplete factorial)
Randomization
Treatment A
Evaluation of Outcomes
Treatment B Treatment A+B None
Adapted from Tinmouth A, Hebert P. Interventional trials: an overview of design alternatives. Transfusion. 2007;47:565-67.
8/13/2019 Biomedical Statistics Johns Hopkins
11/2811Source: Lancet. (1992). 339: 753-70.
ISIS-3 Design
Fibrinolytic agent
SK tPA APSAC
Anti-thrombotic
agent
Aspirin
Aspirin and
heparin
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Factorial Design
Evaluates two interventions simultaneously Four possible treatment combinations
Efficient approach in some circumstances
Potentially more informative approach
Increases proportion getting active treatment
Major concern: interaction of interventions
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Problems with Factorial Design
Patients must be willing and able to take any of the treatmentcombinations
Optimal dose modification strategy for toxicity may be hard to
determine
May require burdensome administration scheme if blinded Interaction complicates interpretation of treatment effects
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Bottom Line on Interaction
You cant rely on detecting modest interactions if studies arepowered for main effects
Interaction is important to study if agents are likely to be used
together
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Crossover Designs
Randomization
Treatment A Treatment B
Treatment A Treatment B
Evaluation of Outcomes
Evaluation of Outcomes
Adapted from Tinmouth A, Hebert P. Interventional trials: an overview of design alternatives. Transfusion. 2007;47:565-67.
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Advantages of Cross-Over Designs
Address question of major interest Will this patient do better on drug A or drug B? Removes patient effect thereby reducing variability and
increasing precision of estimation
Opportunity to receive both treatments (or be assured of receivingactive treatment at some point) is attractive to patients
Under assumption of no carryover effect, design provides more
information than simple parallel design
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Disadvantages of Cross-Over Designs
Assumption of no carryover effects is difficult to test May be difficult to determine appropriate length of washout period
so as to avoid carryover effects
There may be period effects in addition to carryover effects
Progression of disease Dropouts
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Cluster Design
Groups or clusters randomly assigned, not individuals Examples: villages, classrooms, platoons
Randomization
Treatment A
Evaluation of
Outcomes
Treatment B
Adapted from Tinmouth A, Hebert P. Interventional trials: an overview of design alternatives. Transfusion. 2007;47:565-67.
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Study Designs
Treatment allocation method Blinding of assigned treatment
Choice of control group
ICH E10
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In the Next Lecture Section Well Look at . . .
Objectives and hypotheses How to meet objectives Hierarchy of strength of evidence
Phases of trials
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Section B
Objectives and Hypotheses
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In the Beginning
Begin with a clear statement of the major scientific questions posed
by the study, usually conveyed in quantitative terms
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Objectives by Phase
Phase I
Determine optimal or tolerable dose Describe adverse event or PK profile Establish feasibility of treatment approach
Phase II
Estimation of activity
Comparison of doses or schedules
Estimation of factors for Phase III Phase III
Demonstrate superiority or non-inferiority
Estimate rates of adverse events Phase IV Address remaining outstanding issues
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Examples
To select the optimal dose that satisfies specific criteria
To demonstrate that the two year mortality rate on treatment A is
less than on treatment B
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The Objective Is to . . .
Classify
Order
Estimate differences
Estimate rates
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Cohesive Driving Force
All other properties of the trial, the study population, the primary
endpoint, the sample size, the primary analysis, flow from the study
objective
Photo by Dirk Gently via Flickr.com. Creative Commons BY-NC-ND.
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Study Hypotheses
The study objective corresponds to the primary hypothesis of the
study, e.g., the null hypothesis, H0
The two year mortality rate on treatment A equals the two yearmortality rate on treatment B
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