SMART Designs for Developing Adaptive Treatment Strategies S.A. Murphy K. Lynch, J. McKay, D. Oslin & T.Ten Have CPDD June, 2005

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

Adaptive Treatment Strategies are individually tailored treatments, with treatment type and dosage changing with patient 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 Rush et al. (2003) Treatment of Depression

EXAMPLE : Treatment of alcohol dependency. Primary outcome is a summary of heavy drinking scores over time.

GOAL : Provide experimental methods for developing treatment assignment, i.e. decision, rules. Primary Outcome: a summary of drinking scores over time GOAL : How do we design trials so as to develop decision rules that minimize drinking?

The Challenges Delayed Effects ---sequential multiple assignment randomized trials (SMART) Adaptive Treatment Strategies are High Dimensional Multi-component Treatments ---series of developmental, randomized trials prior to confirmatory trial (MOST).

What is a sequential multiple assignment randomized trial (SMART)?

Why a SMART design? 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 is not the best way to construct an adaptive treatment strategy.

Cohort Effects Subjects who will enroll in, who remain in or who are adherent in the trial of the initial treatments may be quite different from the subjects in SMART.

Delayed Effects Negative synergies: An initial treatment may produce a higher proportion of responders but also produce side effects that reduce the effectiveness of subsequent treatments for those that do not respond. Or the burden imposed by this initial treatment may be sufficiently high so that nonresponders are less likely to adhere to subsequent treatments.

Delayed Effects Positive synergies: A treatment may not appear best initially but may have enhanced long term effectiveness when followed by a particular maintenance treatment. Or the initial treatment may lay the foundation for an enhanced effect of subsequent treatments.

Summary: When evaluating and comparing initial treatments we need to take into account the effects of the secondary treatments thus SMART

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

SMART Designing Principles

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.

SMART Designing Principles Choose a primary hypothesis that is both scientifically important and aids in developing the adaptive treatment strategy. EXAMPLE: Hypothesize that given the secondary treatments provided, the initial treatment Med A + psychosocial counseling leads to lower drinking than the initial treatment Med A alone.

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 + EM+ counseling as compared to a change in medication only.

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. Employ MOST to construct an adaptive treatment strategy.

This seminar can be found at: seminars/CPDD0605.ppt This seminar is 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: