SMART Trials for Developing Adaptive Treatment Strategies S.A. Murphy Workshop on Adaptive Treatment Designs NCDEU, 2006

2 Outline Why Adaptive Treatment Strategies? Why SMART trials? Experimental Principles and Analysis

3 Adaptive Treatment Strategies are individually tailored sequences of treatments, with treatment type and dosage is adapted to the patient. Operationalize clinical practice.

4 Why Adaptive Treatment Strategies? –High heterogeneity in response to any one treatment What works for one person may not work for another What works now for a person may not work later –Improvement often marred by relapse –Co-occurring disorders/adherence problems are common

5 Example of an Adaptive Treatment Strategy Treatment of alcohol dependence. Goal is to reduce drinking. Following graduation from the intensive outpatient program the patient is prescribed naltrexone. The patient is monitored weekly over the next two months. If the patient has 2 or more heavy drinking days during this period and is nonadherent then the patient’s medication is augmented by CBI. If the patient has 2 or more heavy drinking days during this period and is adherent then the patient’s medication is switched to acamprosate. If the patient is able to make the entire 2 months with 1 or no heavy drinking days then the patient is continued on naltrexone and the patient is provided telephone disease management.

6 The Big Questions What is the best sequencing of treatments? What is the best timings of alterations in treatments? What information do we use to make these decisions?

7 Why SMART Trials? What is a sequential multiple assignment randomized trial (SMART)? Conceptually a randomization takes place at each critical decision. Goal is to inform the construction of an adaptive treatment strategies.

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9 First Alternate Approach Why not use data from multiple trials to construct the adaptive treatment strategy? Choose the best initial treatment on the basis of a randomized trial of initial treatments and choose the best secondary treatment on the basis of a randomized trial of secondary treatments.

10 Delayed Effects Negative synergies: An initial treatment may produce a higher proportion of responders but also result in side effects that reduce the variety of subsequent treatments for those that do not respond. Positive synergies: A treatment may not appear best initially but may have enhanced long term effectiveness when followed by a particular maintenance treatment.

11 Cohort Effects Subjects who will enroll in, who remain in or who are adherent in the historical trial of the (initial) treatments may be quite different from the subjects in SMART. (D. Oslin’s talk!!)

12 Summary: When evaluating and comparing initial treatments, in a sequence of treatments, we need to take into account the effects of the secondary treatments thus SMART A treatment that appears best in terms of early response may not be the best initial treatment in a sequence of treatments. Standard randomized trials may yield information about different populations from SMART trials.

13 Second Alternate Approach to SMART Why not use theory, clinical experience and expert opinion to construct the adaptive treatment strategy and then compare this strategy against an appropriate alternative in a confirmatory randomized trial? The alternative may be the same strategy but with one component altered.

14 Problems with the two group trials (or repeated cycles of randomized two group trials) Adaptive Treatment Strategies are multi-component treatments: We are not opening the black box— we don’t know why we get or do not get significance and Heavy reliance on expert opinion or best guesses -- to choose not only the components but how to sequence them and when to switch. L. Collins Talk!!

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16 SMART Designing Principles

17 SMART Designing Principles KEEP IT SIMPLE: At each stage, restrict class of treatments only by ethical, feasibility or strong scientific considerations. Use a summary (responder status) instead of all intermediate outcomes (time until nonresponse, adherence, burden, stress level, etc.) to restrict class of next treatments. Collect intermediate outcomes that might be useful in ascertaining for whom each treatment works best; information that might enter into the adaptive treatment strategy.

18 SMART Designing Principles Choose primary hypotheses that are both scientifically important and aid in developing the adaptive treatment strategy. Power trial to address these hypotheses.

19 SMART Designing Principles: Primary Hypothesis EXAMPLE 1: (sample size is highly constrained): Hypothesize that given the secondary treatments provided, the initial treatment Med A + CBT leads to lower drinking than the initial treatment Med A alone. EXAMPLE 2: (sample size is less constrained): Hypothesize that a particular adaptive treatment strategy beginning with Med A+ CBT results in lower drinking than a particular adaptive treatment strategy beginning with Med A.

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22 SMART Designing Principles Choose secondary hypotheses that further develop the adaptive treatment strategy and use the randomization to eliminate confounding. EXAMPLE: Hypothesize that non-adhering non- responders will have lower drinking if provided a change in medication + CBT + EM as compared to a change in medication only.

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24 Discussion Secondary analyses can use patient characteristics/outcomes to provide evidence for a more sophisticated adaptive treatment strategy. (when and for whom?) SMART design and analyses targeted at scientific goal of informing the construction of a high quality adaptive treatment strategy

25 This seminar can be found at: seminars/NCDEU0606.ppt This seminar is partially based on a paper with Kevin Lynch, Jim McKay, David Oslin and Tom Ten Have. me with questions or if you would like a copy:

26 Examples of “SMART” designs: CATIE (2001) Treatment of Psychosis in Alzheimer’s Patients CATIE (2001) Treatment of Psychosis in Schizophrenia STAR*D (2003) Treatment of Depression Thall et al. (2000) Treatment of Prostate Cancer Oslin (on-going) Treatment of Alcohol Dependence