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Experimental Designs for DevelopingAdaptive Treatment Strategies

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

Society of Behavioral Medicine, Washington, DCApril 26, 2011

Almirall, Compton, Murphy Designs for Developing Adaptive Treatment Strategies

Adaptive Treatment StrategiesSequential Multiple Assignment Randomized Trial (SMART)

SMART Design PrinciplesDiscussion

Outline

Adaptive Treatment StrategiesWhat? Why?ATS Development Considerations

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

SMART Design PrinciplesKeep it SimpleChoosing Primary and Secondary Hypotheses

Discussion




What? Why?ATS Development Considerations

Definition of an Adaptive Treatment Strategy

An adaptive treatment strategy (ATS) is a sequence ofindividually tailored decision rules that specify whether, how,and when to alter the intensity, type, dosage, or delivery oftreatment at critical decision points in the medical care process.

ATSs operationalize sequential decision making with the aim ofimproving clinical practice.





Concrete Example of an Adaptive Treatment StrategyPediatric 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.





Why Adaptive Treatment Strategies?Necessary because...

I The chronic nature of 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





Why Adaptive Treatment Strategies?Can be used to inform how to best...

I Adapt treatment to a patient’s chronic/changing courseI Deliver appropriate treatment when needed mostI React to non-adherence or side-effect profilesI Reduce treatment burden; only what is necessaryI Deliver early treatments with positive downstream effectsI Sift through available treatment options

I ⇒ More personalized care, over timeI ⇒ Improving clinical practice





Developing an ATS Requires Careful ConsiderationI For who are we developing the adaptive strategy?

Population, or Context, question.

I What is the goal of the adaptive treatment strategy?Objectives question.

I What is the optimal sequencing of treatments?Sequencing question.

I When do we switch, augment, or maintain treatment?Timing question.

I Based on what information do we make decisions?Tailoring question.


What is a tailoring variable?A time-varying measure that prescribes one treatment at one level and anothertreatment at another level.

Mea

n A

nxi

ety

Sco

re

Adherence to medication relative to CBT

Among responders to combination CBT + MED:

More adherence to CBT More adherence to MED

Step Down to CBT Only

Maintain CBT+MED



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 are randomized to a set of

treatment optionsI Treatment options at randomization may be restricted

depending on intermediate outcome/treatment history

I The goal of a SMART is to inform the development ofadaptive treatment strategies.


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

An ATS for Child Anxiety Within the SMART



Step Down: CBT Only R Maintain:

CBT



Responders R

Responders

Non-Responders R

O2 + Primary


Another ATS for Child Anxiety Within the SMART



Step Down: CBT Only

R Maintain:

CBT



Responders R

Responder

s

Non-Responders R

O2 + Primary




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 Optimal ATS





Keep It Simple, StraightforwardOverarching Principle

At each stage, or critical decision point,...I Restrict class of treatment options by ethical, feasibility, or

strong scientific considerations

I Use low dimensional summary to restrict subsequenttreatments

I Ex: Use S = binary responder status

I Collect rich set of outcomes for tailoringI Information useful for more complex ATSsI Think time-varying effect moderators





SMART Design: Primary Aims

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

Power the SMART to test this hypothesis.


Primary Aim Example 1What is the main effect of first-line treatment?




CBT


Switch Treatmnt: MED

Responders R

Responders

Non-Responders R

O2 + Primary


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

Primary Aim Example 1What is the main effect of first-line treatment?




CBT


Switch Treatmnt: MED

Responders R

Responders

Non-Responders R

O2 + Primary


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

Primary Aim Example 2Which is the best of two fully-operationalized adaptive treatment strategies?




CBT



Responders R

Responder

s

Non-Responders R

O2 + Primary





SMART Design: Secondary Aims

Choose secondary aims/questions that further develop theATS and take advantage of sequential randomization toeliminate confounding.





Secondary Aim Example 1Second-line treatment tailoring aim.

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

Add Treatment: CBT + MED


Non-Responders R

O2 + Primary

Tailoring Variable First-line Txt Second-line Txt Y

CBT


Secondary Aim Example 2Develop a more deeply tailored adaptive treatment strategy.



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…




Examples SMART DesignsExamples of SMART designs which have been funded

I Pelham Study (primary analysis) Treatment of ADHD

I Oslin Study (primary analysis) Treatment of AlcoholDependence

I Jones Study (in field) Treatment for Pregnant Women whoare Drug Dependent

I Kasari Study (in field) Treatment of Children with Autism

I McKay Studies (2 in field) Treatment of Alcohol andCocaine Dependence




Messages, Misconceptions, Misunderstandings

I Distinction between the ATS vs the SMARTI Adaptive Trial? or Adaptive Treatment?

I SMARTs do not necessarily require larger sample sizes

I Distinction btwn adaptive vs non-adaptive treatments

I “Adaptive Design” has other meanings in trials literatureI In SMART, same patients participate in multiple stages

I SMARTs can be seen as developmental trials


TOMORROW, WEDNESDAY 4/27I 3-Hour Workshop on Adaptive Treatment Strategies and

SMART designsI Instructors: Susan A. Murphy and Daniel AlmirallI 3:10-6:00PM following Linda Collins’ workshop on MOSTI Georgetown East, Concourse Level

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

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

Extra Slides


Adaptive Treatment for Children with ADHDB. 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

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 ATSsI 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 ATSThree 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 treatment strategy based on a myopic,local, study-to-study point of view may not be optimal.


Why Not Use Multiple Trials to Construct an ATSConcern 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 ATSConcern 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 ATSConcern 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 ATSConcern 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 treatment

strategies 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


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