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Study Designsfor Adaptive Treatments
• Goal: Develop efficacious and effective adaptive treatment strategies.
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Study Designs
Black Box Study: Randomized comparison between two or more strategies +
1. Dismantling analyses or
2. Further dismantling studies.
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Study Designs
Prospectively develop adaptive treatment strategies using
3. multiple randomized studies or
4. one sequentially within-person randomized study.
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Study Designs
Equipoise Stratification
• improve adherence
• structure future adaptive treatment strategies
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Our speakers….
• Dr. TenHave (Black box and Multiple randomized studies)
• Dr. Lavori (Equipoise Stratification)
• Dr. Murphy (Sequential within-person randomized study)
Ten Have
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Hierarchy of Study Designs
Black Box StudyDismantling Analyses
- Analysis assumptions unfeasible
Unintended negative consequences with burdensome early components
Black Box StudyDismantling Studies
ProspectiveMulitple Studies
Equipoise Stratification
Sequential Within-person Randomization
Analysis assumptions not as unfeasible, but still restrictive
- Analysis assumptions very feasible
- Patient/provider preference addressed
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Randomized comparison between two or more adaptive strategies +
Dismantling analyses or
Further dismantling studies.
Black Box Studies
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Black Box Studies
Unintended negative effects Burdensome first component precludes
compliance with subsequent components
Significant first component effect negates need to study subsequent components already implemented
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Black Box Studies
Waste funds or suffer reduced power in the
first study if the components in the black
box treatment are not put together in an
optimal way.
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Black Box Study+Dismantling Analysis
Analysis problems with dismantling individual components
Current approaches (SEM, LISREL, PATH, mediator analyses) are observational analyses.
More sophisticated approaches still require untestable assumptions.
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Black Box Study+Dismantling Studies
Can take away first components and see:
If the remaining components still produce the effect sizes seen in the black box study
If adherence is improved
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Black Box Study+Dismantling Studies
Black box study may have a null effect
due to poor adherence or because some components have negative interactions.
Then it may be hard to obtain funding for dismantling studies.
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Prospective Multiple Studies
Prospectively develop adaptive treatment strategies using
Multiple randomized studies or
One sequentially within-person randomized study.
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Prospective Multiple Studies
• Discover unintended negative effects prior to running a large scale randomized study of a complex intervention.
• Optimize our complex intervention.
• Use prior studies that provide evidence for the primary treatment.
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Prospective Multiple StudiesIn contrast to black box studies:
Randomization is used at each step to develop the components of an adaptive treatment strategy
However, assumptions still needed for investigating a sequence of treatments or a primary treatment followed by
maintenance or aftercare treatment.
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Prospective Multiple Studies
Nonetheless, possible benefits:
Less waste
Higher quality research at each decision step because each step draws the full attention of full study effort
A more powerful “final” study of optimized treatment vs. usual care.
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Sequentially within-person randomized studies
Goal: Estimate best rules for tailoring treatment in an adaptive treatment strategy.
Murphy
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Sequentially within-person randomized studies
• What are these designs?
• Why use these designs?
• What can I do with them?
• Example
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What are these designs?
• At each time, treatment may be changed, randomize individual to one of a class of possible alternatives.
– Classes of alternative treatments determined by response to past treatment and other ongoing information.
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Why use these designs?
• Interactions between subsequent treatments
• Compositional effects due to prior treatments
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Why use these designs?
• Front line treatment experimentally validated only when “usual care” or “treatment as usual” is secondary (aftercare or maintenance) treatment.
• The sequencing of treatments may make a difference
• Delayed or Cumulative Effects
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Why use these designs?
Compositional effects are particularly important if we believe that both response to initial treatment and adherence to initial treatment should influence the choice of subsequent treatments.
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Example of a Study in Development
Population: Cocaine abusing women with risky sexual practices.
Goal: Reduce risky sexual practices.
Subgoal: Find a good treatment strategy to achieve goal!
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Sequentially Within-Person Randomized Studies
• CATIE Schizophrenia Study
• CATIE Alzheimer Study
• STAR*D
• ALLHAT
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To Think About:
• In each design we may restrict the class of secondary treatments based on patient information during initial treatment.
• What variables should be used to determine the classes of secondary treatments?
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To Think About: :
– Cocaine example uses responder status and adherence to determine the class of treatments.
– CATIE uses responder status, tolerance and past treatment to determine the class of treatments.
– STAR*D uses responder status, patient/clinical preference and past treatment to determine the class of treatments.
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To Think About:
• What are the consequences of restricting the class of treatments?
• These restrictions structure the resulting adaptive treatment strategies.