1. An Experimental Paradigm for Developing Adaptive Treatment Strategies S.A. Murphy Univ. of Michigan ACSIR, July, 2003

2. Setting: Management of chronic, relapsing disorders such as alcohol, cocaine addiction and mental illness Characteristics: Improvement marred by relapse May need a sequence of treatments prior to improvement Intervals during which more intense treatment is required alternate with intervals in which less treatment is sufficient

3. Adaptive Treatment Strategies are individually tailored treatments, with treatment type and dosage changing with ongoing subject need. Mimic Clinical Practice. Brooner et al. (2002) Treatment of Cocaine Addiction Breslin et al. (1999) Treatment of Alcohol Addiction Prokaska et al. (2001) Treatment of Tobacco Addiction Unützer et al. (2001) Treatment of Depression

4. GOAL : Provide experimental methods for developing treatment assignment, i.e. decision, rules. Response: a summary of depression scores over time GOAL : How do we design trials so as to develop decision rules that minimize the mean response, mean of summarized depression score?

7. Two Challenges Delayed Effects ---sequential within person randomization Adaptive Treatment Strategies are High Dimensional Multi-component Treatments ---series of developmental trials prior to confirmatory trial.

8. Delayed Effects Or, why choosing the best initial treatment on the basis of a randomized trial of initial treatments and choosing the best secondary treatment on the basis of a randomized trial of secondary treatments will not provide the best adaptive treatment strategy.

11. Summary: Determining the best initial treatment requires that we first calculate the mean responses of patients for each combination of secondary treatment, intermediate outcome and initial treatment. The main point : If these mean responses to secondary treatment vary by initial treatment then we need to use sequentially within-person randomization.

12. When would the mean responses of patients for each combination of secondary treatment, intermediate outcome and initial treatment vary by initial treatment?

15. Delayed Effects: The Bottom Line Are there unobserved but potentially important common causes of the response and intermediate outcome? Are there unobserved but potentially important causal pathways from initial treatment to final response? If yes to either of the above then use sequentially within-person randomized trials to develop good adaptive treatment strategies.

16. Adaptive Treatment Strategies are High Dimensional Multi-Component Treatments when to start treatment? which treatment to start? when to step-up treatment? which step-up treatment? when to step down treatment to maintenance/monitoring? which maintenance/monitoring treatment? what information to use to make each of the above decisions?

17. Meeting the Challenges Delayed Effects: Sequential within-person randomization: Randomize at each decision point. High Dimensionality: Series of developmental randomized trials prior to a confirmatory trial (Box, Hunter and Hunter,1978, pg. 303).

18. Principles in Designing a Sequentially Within-Person Randomized Trial At each decision point, restrict class of treatments only by ethical, feasibility or strong scientific considerations. Use a low dimension summary (responder status) instead of all intermediate outcomes (time until nonresponse, adherence, burden, stress level, etc.) to restrict class of treatments. Collect intermediate outcomes that might be useful in ascertaining for whom each treatment works best; information that might enter into the decision rules.

19. Principles in Designing a Sequentially Within-Person Randomized Trial Choose a primary hypothesis that is both scientifically important and aids in developing the adaptive treatment strategy. Choose secondary hypotheses that further develop the adaptive treatment strategy and use the randomization to eliminate confounding.

21. Primary Hypothesis: Do adaptive treatment strategies beginning with med A produce different depression responses than adaptive treatment strategies beginning with med B? Analysis: Compare estimated mean responses for each of the 4 adaptive treatment strategies beginning with txt A to the mean responses for each of the 4 adaptive treatment strategies beginning with txt B. Power developmental trial to address this question; formulae in my paper.

22. Analyses that do not aid in the development of adaptive treatment strategies! 1)Decide whether initial treatment A is better than initial treatment B by comparing intermediate outcomes (responder status). 2)Decide whether initial treatment A is better than initial treatment B by comparing mean response ignoring the secondary treatments.

23. Secondary Hypotheses Compare adaptive treatment strategies that begin with the same treatment; i.e. compare response to secondary treatments by levels of the summary intermediate outcome. Use an analysis that tests if other intermediate outcomes differentiate for whom each secondary treatment is best and if any pretreatment information differentiates for whom each initial treatment is best.

24. How might this work out? 1.Use sample size so as to power the primary analysis with type I error of.1 and power of.9. 2.In the primary analysis calculate the mean response for each adaptive treatment strategies (4 with initial treatment A; 4 with initial treatment B. Compare best treatment strategy beginning with treatment A with best treatment strategy beginning with B. 3.Suppose best treatment strategy beginning with A produces a smaller mean depression response than best treatment strategy beginning with B.

25. How might this work out? 1.In secondary analyses, we find that the intermediate outcome “adherence during initial treatment” differentiates between med A nonresponders who are assigned med B versus EM + med B+ psychosocial. 2.In secondary analyses, we see no difference between med A responders who are assigned med A versus med A+ counseling. Recall study not powered for these secondary analyses.

26. How might this work out? In second developmental trial, provide treatment A to all patients. If responder, randomly assign med A versus med A+counseling. If nonresponder, randomly assign med B versus EM+med B+ psychosocial counseling versus EM +med B. Power study for both of these analyses. Use proportions of responding/ nonresponding from prior developmental trial.

27. How might this work out? We see no difference in depression scores between secondary treatments for responders. We confirm the interaction: nonresponding-nonadherers benefit more from EM + med B than med B alone whereas nonresponding-adherers benefit the same amount from EM+ med B as from med B. A comparison of EM+ med B versus EM + med B + psychosocial indicates no benefit of psychosocial counseling above and beyond EM+ med B.

28. How might this work out? Confirmatory study of two groups. 1)Treatment Strategy: Assign med A initially. If responder continue on med A; if nonresponder- nonadherer assign EM+med B; if nonresponder- adherer assign med B. Versus 2) Standard Care.

29. Discussion Trial design and analyses targeted at scientific goal. Increased confidence that developed adaptive treatment strategy will be better than standard care (increased power). Lower chance of wanting/needing to change treatment decision rules midway through confirmatory trial.

30. This seminar can be found at http://www.stat.lsa.umich.edu/~samurphy/nida/seminars.html