1 Section IV Study Designs for Investigating Adaptive Treatment Strategies Murphy

2 Study Designs for Adaptive Treatments Goal: Develop efficacious and effective adaptive treatment strategies.

3 Study Designs Black Box Study: Randomized comparison between two or more strategies +  Dismantling analyses or  Further dismantling studies.

4 Study Designs Prospectively develop adaptive treatment strategies using  multiple randomized studies or  one sequentially within-person randomized study.

5 Study Designs Equipoise Stratification improve adherence structure future adaptive treatment strategies

6 Our speakers…. Dr. TenHave (Black box and Multiple randomized studies) Dr. Lavori (Equipoise Stratification) Dr. Murphy (Sequential within-person randomized study) Ten Have

7 TenHave: Ten Have

8 Hierarchy of Study Designs Black Box Study Dismantling Analyses - Analysis assumptions unfeasible Unintended negative consequences with burdensome early components Black Box Study Dismantling Studies Prospective Mulitple Studies Equipoise Stratification Sequential Within-person Randomization Analysis assumptions not as unfeasible, but still restrictive - Analysis assumptions very feasible - Patient/provider preference addressed

9 Randomized comparison between two or more adaptive strategies +  Dismantling analyses or  Further dismantling studies. Black Box Studies

10 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

11 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.

12 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.

13 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

14 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.

15 Prospective Multiple Studies Prospectively develop adaptive treatment strategies using  Multiple randomized studies or  One sequentially within-person randomized study.

16 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.

17 Prospective Multiple Studies In 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.

18 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.

19 Phil Lavori:

20 Susan Murphy:

21 Sequentially within-person randomized studies Goal: Estimate best rules for tailoring treatment in an adaptive treatment strategy. Murphy

22 Sequentially within-person randomized studies What are these designs? Why use these designs? What can I do with them? Example

23 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.

24 What are these designs? Each individual may be randomized multiple times.

25 Why use these designs? Interactions between subsequent treatments Compositional effects due to prior treatments

26 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

27 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.

28 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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30 What can I do with it? Compare adaptive treatment strategies. There are 4 strategies:

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33 Sequentially Within-Person Randomized Studies CATIE Schizophrenia Study CATIE Alzheimer Study STAR*D ALLHAT

34 STAR*D

35 CATIE

36 To Think About: Could we use these designs to develop “encouragement to adhere” strategies?

37 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?

38 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.

39 To Think About: What are the consequences of restricting the class of treatments? These restrictions structure the resulting adaptive treatment strategies.

40 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?