SMART Trials for DevelopingAdaptive Treatment Strategies
S.A. Murphy
Workshop on Adaptive Treatment Designs
NCDEU, 2006
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Outline
•Why Adaptive Treatment Strategies?
•Why SMART trials?
•Experimental Principles and Analysis
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Adaptive Treatment Strategies are individually tailoredsequences of treatments, with treatment type and dosageis adapted to the patient. Operationalize clinicalpractice.
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Why Adaptive Treatment Strategies?
–High heterogeneity in response to any onetreatment
•What works for one person may not work foranother
•What works now for a person may not work later
–Improvement often marred by relapse
–Co-occurring disorders/adherence problems arecommon
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Example of an Adaptive Treatment Strategy
Treatment of alcohol dependence. Goal is to reduce drinking.
Following graduation from the intensive outpatient program thepatient is prescribed naltrexone. The patient is monitored weeklyover the next two months. If the patient has 2 or more heavydrinking days during this period and is nonadherent then thepatient’s medication is augmented by CBI. If the patient has 2 ormore heavy drinking days during this period and is adherent thenthe patient’s medication is switched to acamprosate. If the patientis able to make the entire 2 months with 1 or no heavy drinkingdays then the patient is continued on naltrexone and the patient isprovided telephone disease management.
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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?
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Why SMART Trials?
What is a sequential multiple assignment randomizedtrial (SMART)?
Conceptually a randomization takes place at eachcritical decision.
Goal is to inform the construction of an adaptivetreatment strategies.
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First Alternate Approach
•Why not use data from multiple trials to construct theadaptive treatment strategy?
• Choose the best initial treatment on the basis of arandomized trial of initial treatments and choose thebest secondary treatment on the basis of arandomized trial of secondary treatments.
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Delayed Effects
Negative synergies: An initial treatment may produce ahigher proportion of responders but also result in sideeffects that reduce the variety of subsequenttreatments for those that do not respond.
Positive synergies: A treatment may not appear bestinitially but may have enhanced long termeffectiveness when followed by a particularmaintenance treatment.
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Cohort Effects
Subjects who will enroll in, who remain in or whoare adherent in the historical trial of the (initial)treatments may be quite different from the subjects inSMART.
(D. Oslin’s talk!!)
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Summary:
•When evaluating and comparing initial treatments, in asequence of treatments, we need to take into account theeffects of the secondary treatments thus SMART
•A treatment that appears best in terms of earlyresponse may not be the best initial treatment in asequence of treatments.
•Standard randomized trials may yield informationabout different populations from SMART trials.
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Second Alternate Approach to SMART
Why not use theory, clinical experience and expertopinion to construct the adaptive treatment strategyand then compare this strategy against an appropriatealternative in a confirmatory randomized trial?
The alternative may be the same strategy but with onecomponent altered.
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Problems with the two group trials (or repeated cyclesof randomized two group trials)
•Adaptive Treatment Strategies are multi-componenttreatments:
•We are not opening the black box— we don’t knowwhy we get or do not get significance and
•Heavy reliance on expert opinion or best guesses --to choose not only the components but how tosequence them and when to switch.
L. Collins Talk!!
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SMART Designing Principles
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SMART Designing Principles
•KEEP IT SIMPLE: At each stage, restrict class oftreatments only by ethical, feasibility or strong scientificconsiderations. Use a summary (responder status)instead of all intermediate outcomes (time untilnonresponse, adherence, burden, stress level, etc.) torestrict class of next treatments.
•Collect intermediate outcomes that might be useful inascertaining for whom each treatment works best;information that might enter into the adaptive treatmentstrategy.
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SMART Designing Principles
•Choose primary hypotheses that are both scientificallyimportant and aid in developing the adaptive treatmentstrategy.
•Power trial to address these hypotheses.
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SMART Designing Principles:
Primary Hypothesis
•EXAMPLE 1: (sample size is highly constrained):Hypothesize that given the secondary treatmentsprovided, the initial treatment Med A + CBT leads tolower drinking than the initial treatment Med A alone.
•EXAMPLE 2: (sample size is less constrained):Hypothesize that a particular adaptive treatment strategybeginning with Med A+ CBT results in lower drinkingthan a particular adaptive treatment strategy beginningwith Med A.
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SMART Designing Principles
•Choose secondary hypotheses that further develop theadaptive treatment strategy and use the randomizationto eliminate confounding.
•EXAMPLE: Hypothesize that non-adhering non-responders will have lower drinking if provided achange in medication + CBT + EM as compared to achange in medication only.
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Discussion
•Secondary analyses can use patientcharacteristics/outcomes to provideevidence for a more sophisticated adaptivetreatment strategy. (when and for whom?)
•SMART design and analyses targeted atscientific goal of informing the constructionof a high quality adaptive treatment strategy
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This seminar can be found at:
http://www.stat.lsa.umich.edu/~samurphy/
seminars/NCDEU0606.ppt
This seminar is partially based on a paper with KevinLynch, Jim McKay, David Oslin and Tom TenHave. Email me with questions or if you would likea copy:
samurphy@umich.edu
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Examples of “SMART” designs:
•CATIE (2001) Treatment of Psychosis in Alzheimer’sPatients
•CATIE (2001) Treatment of Psychosis inSchizophrenia
•STAR*D (2003) Treatment of Depression
•Thall et al. (2000) Treatment of Prostate Cancer
•Oslin (on-going) Treatment of Alcohol Dependence