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Section IV

Study Designs for Investigating Adaptive Treatment Strategies

Murphy

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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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TenHave:

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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Phil Lavori:

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Susan Murphy:

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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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What are these designs?

• Each individual may be randomized multiple times.

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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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What can I do with it?

Compare adaptive treatment strategies.

There are 4 strategies:

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Sequentially Within-Person Randomized Studies

• CATIE Schizophrenia Study

• CATIE Alzheimer Study

• STAR*D

• ALLHAT

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STAR*D

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CATIE

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To Think About:

• Could we use these designs to develop “encouragement to adhere” strategies?

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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.

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To Think About:

• Should any of these designs be followed by a confirmatory randomized control trial; that is, are these designs primarily hypothesis generating and treatment strategy building designs?