Getting SMART About Developing Individualized Sequences ...dalmiral/slides/CPDD_ALMIRALL.pdf1.Concern 1: Delayed Therapeutic Effect 2.Concern 2: Diagnostic Effects 3.Concern 3: Cohort

Getting SMART About Developing IndividualizedSequences of Health Interventions

Introduction to Adaptive Interventions and SMART Designs8:05-8:35PM, Daniel Almirall and Susan Murphy, UMich

Q&A: 8:35-8:40PM

Adaptive Approach to Naltrexone Treatment for Alcoholism8:40-9:10PM, David Oslin and Kevin Lynch, UPenn

Q&A: 9:10-9:15PM

Testing Variants of Treatments for Substance UseDisorders During Pregnancy

9:15-9:45PM, Hendree Jones, RTI

Q&A and Discussion: 9:45-10:00PM

Introduction to Adaptive Interventions andSMART Study Design Principles

Daniel Almirall1,2 Scott N Compton3

Susan A Murphy1,2,4

1Institute for Social Research, University of Michigan2The Methodology Center, Penn State University

3Psychiatry and Behavioral Sciences, Duke University Medical Center4Department of Statistics, University of Michigan

Getting SMART About Developing Individualized Sequencesof Health Interventions, CPDD, Hollywood, Florida

June 22, 2011

Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions

Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)

SMART Design PrinciplesDiscussion

Disclosures or Conflicts of Interest: None

Disclosures or Conflicts of Interest

None




Outline

Adaptive InterventionsWhat? Why?

Sequential Multiple Assignment Randomized Trial (SMART)What are SMARTs?

SMART Design PrinciplesKeep it SimpleChoosing Primary and Secondary Hypotheses

Discussion




What? Why?

Definition: An Adaptive Intervention is

I a sequence of individually tailored decision rulesI that specify whether, how, and/or whenI to alter the intensity, type, dosage, or delivery of treatmentI at critical decision points in the course of care.

Adaptive Interventions operationalize sequential decisionmaking with the aim of improving clinical practice.




What? Why?

Concrete Example of Adaptive InterventionPediatric Anxiety Example (SAD, GAD, SoP)

Maintain: CBT

CBT

Add Treatment: CBT + MED

Responder

s

Non-Responders

Tailoring Variable First-line Txt Second-line Txt

I Goal is to minimize the child’s symptom profile/trajectory.




What? Why?

What makes up an Adaptive Intervention?1. Critical decisions: treatment options and more2. Tailoring variables: to decide how to adapt treatment3. Decision rules: inputs tailoring variable, outputs one or

more recommended treatments

Maintain: CBT

CBT


Responder

s

Non-Responders

Tailoring Variable First-line Txt Second-line Txt

Adaptive interventions AKA: dynamic treatment regimes, adaptive treatmentstrategies, treatment algorithms, structured treatment interruptions, practiceparameters, ASAM criteria...




What? Why?

Why Adaptive Interventions?Necessary because...

I Chronic nature of substance use/mental health disorders

I Waxing and waning course (multiple relapse, recurrence)I Genetic and non-genetic factors influence courseI Co-occuring disorders may arise

I High patient heterogeneity in response to treatment

I Within person (over time) differential response to treatmentI Between person differential response to treatment

All require a sequences of treatment decisions.




What are SMARTs?

What is a Sequential Multiple AssignmentRandomized Trial (SMART)?

I Multi-stage trials; same participants throughoutI Each stage corresponds to a critical decision pointI At each stage, subjects randomized to set of treatment

optionsI The goal of a SMART is to inform the development of

adaptive interventions.

I will give you an example SMART, but first...




What are SMARTs?

Motivation for an Example SMARTChild-Adolescent Anxiety Multi-modal Study (CAMS)

I CAMS: acute-phase, efficacy, RCT for child anxiety

I CBT+MED > MED ≈ CBT > Placebo

I However, some families and clinicians remain concernedabout the use of MED in this population

I So an important next question for clinical practice is“Can we delay the use of MED?”

I Some children may do fine w/ CBT only and not need MED.


Concrete Example of a SMART: Pediatric Anxiety

Add Treatment: CBT + MED + FT Non-Responders

CBT + MED Maintain: CBT + MED

Step Down: CBT Only

R Maintain:

CBT

CBT Add Treatment: CBT + MED

Switch Treatment: MED

Responders R

Responders

Non-Responders R

O2 + Primary

Tailoring Variable First-line Txt Second-line Txt Y O1

One Adaptive Intervention Within the SMART



Step Down: CBT Only R Maintain:

CBT



Responders R

Responders

Non-Responders R

O2 + Primary


Another Adaptive Intervention Within the SMART



Step Down: CBT Only

R Maintain:

CBT



Responders R

Responder

s

Non-Responders R

O2 + Primary


4 Embedded Adaptive Interventions in this SMART

Add Treatment:CBT + MED + FTNon‐Responders

CBT + MED Step Down:CBT Boost

Responders

Add Treatment:CBT + MED + FT Non‐Responders

CBT + MED Maintain:CBT + MED

Responders

Maintain:CBT BoostResponders

CBT Add Treatment:

CBT + MEDNon‐Responders

Maintain:CBT BoostResponders

CBT Switch Treatment:

MEDNon‐Responders

AI 1

AI 2

AI 3

AI 4



Keep it SimpleChoosing Primary and Secondary Hypotheses

SMART Design Principles

I KISS Principle: Keep It Simple, Straightforward

I Power for simple important primary hypotheses

I Take Appropriate steps to develop an moredeeply-individualized Adaptive Intervention





Keep It Simple, StraightforwardOverarching Principle

At each stage, or critical decision point,...I Use low dimensional summary to restrict subsequent

treatmentsI Use binary responder statusI Should be easy to use in actual clinical practice

I Restrict class of treatment options by ethical, feasibility, orstrong scientific considerations

I Collect additional, auxiliary time-varying measuresI To develop a more deeply-tailored Adaptive InterventionI Think time-varying effect moderators





SMART Design: Primary Aims

Choose a simple primary aim/question that aids developmentof an adaptive intervention.

Power the SMART to test this hypothesis.


Primary Aim Example 1What is the main effect of first-line treatment? End of study outcome (e.g., ANOVA).




CBT


Switch Treatmnt: MED

Responders R

Responders

Non-Responders R

O2 + Primary


PowerES N0.8 520.5 1280.2 788α = 0.05β = 0.20

Primary Aim Example 2What is the main effect of first-line treatment? Longitudinal outcome (e.g., LMM).




CBT


Switch Treatmnt: MED

Responders R

Responders

Non-Responders R

O2 + Primary


PowerES N0.8 340.5 830.2 505ρ = 0.60α = 0.05β = 0.20




SMART Design: Secondary Aims

Choose secondary aims/questions that further develop theAdaptive Intervention and take advantage of sequentialrandomization to eliminate confounding.





Secondary Aim Examples 1 and 2Second-line treatment tailoring aim.

O2 = CBT adherence, time to non-response, allegiance with therapist, changes in home environment



Non-Responders R

O2 + Primary

Tailoring Variable First-line Txt Second-line Txt Y

CBT


Secondary Aim Example 3Build a more deeply tailored adaptive intervention.



Step Down: CBT Only

R Maintain:

CBT



Responders R

Responders

Non-Responders R

O2 + Primary


O1 = demographics, genetics, sub-diagnoses, co-morbidities, etc…

O2 = adherence, time to NR, changes at home, etc…



Take Home the Following

I Adaptive Interventions individualize treatment up-front andthroughout

I Adaptive Interventions are guides for clinical practice

I SMARTs do not necessarily require larger sample sizes

I SMARTs are used to build better Adaptive InterventionsI Next trial compares SMART-optimized Adaptive

Intervention vs. state-of-the-art treatment


Adaptive Treatment for Children with ADHDPI: Pelham, Florida International University

Continue Medication Responders

Medication Increase Medication Dose

Add Behavioral Intervention

R Continue

Behavioral Intervention Behavioral

Intervention Increase Behavioral

Intervention

Add Medication

Non-Responders R

Responders

Non-Responders R



Thank you! Questions?

Email me with questions about this presentation:I [email protected]

These slides will be posted on my website:I http://www-personal.umich.edu/∼dalmiral/


Extra Slides


Treatment for Alcohol DependenceD. Oslin, University of Pennsylvania

Early Trigger for NR: 2+ HDD CBI

CBI + Naltrexone

R

Late Trigger for NR: 5+ HDD

CBI

CBI + Naltrexone

Non-Response R

Non-Response R

Naltrexone

TDM + Naltrexone

8 Week Response R

Naltrexone

TDM + Naltrexone

8 Week Response R

Other Alternatives

I Piecing Together Results from Multiple TrialsI Choose best first-line treatment on the basis of a two-arm

RCT; then choose best second-line treatment on the basisof another separate, two-arm RCT

I Concerns: delayed therapeutic effects, and cohort effects

I Observational (Non-experimental) Comparisons of AIsI Using data from longitudinal randomized trialsI May yield results that inform a SMART proposalI Understand current treatment sequencing practicesI Typical problems associated with observational studies

I Expert Opinion


Why Not Use Multiple Trials to Construct an AIThree Concerns about Using Multiple Trials as an Alternative to a SMART

1. Concern 1: Delayed Therapeutic Effect

2. Concern 2: Diagnostic Effects

3. Concern 3: Cohort Effects

All three concerns emanate from the basic idea thatconstructing an adaptive intervention based on a myopic, local,study-to-study point of view may not be optimal.


Why Not Use Multiple Trials to Construct an AIConcern 1: Delayed Therapeutic Effects, or Sequential Treatment Interactions

Positive Synergy Btwn First- and Second-line Treatments

Tapering off medication after 12 weeks of use may not appearbest initially, but may have enhanced long term effectivenesswhen followed by a particular augmentation, switch, ormaintenance strategy.

Tapering off medication after 12 weeks may set the child up forbetter success with any one of the second-line treatments.


Why Not Use Multiple Trials to Construct an AIConcern 1: Delayed Therapeutic Effects, or Sequential Treatment Interactions

Negative Synergy Btwn First- and Second-line Treatments

Keeping the child on medication an additional 12 weeks mayproduce a higher proportion of responders at first, but may alsoresult in side effects that reduce the variety of subsequenttreatments available if s/he relapses.

The burden associated with continuing medication an additional12 weeks may be so high that non-responders will not adhereto second-line treatments.


Why Not Use Multiple Trials to Construct an AIConcern 2: Diagnostic Effects

Tapering off medication after 12 weeks initial use may notproduce a higher proportion of responders at first, but may elicitsymptoms that allow you to better match subsequent treatmentto the child.

The improved matching (personalizing) on subsequenttreatments may result in a better response overall as comparedto any sequence of treatments that offered an additional 12weeks of medication after the initial 12 weeks.


Why Not Use Multiple Trials to Construct an AIConcern 3: Cohort Effects

I Children enrolled in the initial and secondary trials may bedifferent.

I Children who remain in the trial(s) may be different.I Characteristics of adherent children may differ from study

to study.I Children that know they are undergoing adaptive

interventions may have different adherence patterns.

Bottom line: The population of children we are makinginferences about may simply be different from study-to-study.


SMART Design PrinciplesChoose a Longitudinal Response Measure

Why choose a longitudinal outcome, or a with-in personsummary of outcomes over time?

I These are chronic disorders (e.g., child-hood onset anxietydisorder)

I Outcome should incorporate time to initial response as acomponent

I Quick initial relief of symptoms should be valued


Documents

Getting SMART About Developing Individualized Sequences ...dalmiral/slides/CPDD_ALMIRALL.pdf1.Concern 1: Delayed Therapeutic Effect 2.Concern 2: Diagnostic Effects 3.Concern 3: Cohort